Four-component cascade heteroannulation of heterocyclic ketene aminals: Synthesis of functionalized tetrahydroimidazo[1,2- a ]pyridine derivatives

Article abstract of DOI:10.1021/jo3013836

An efficient and straightforward four-component synthetic protocol has been developed to synthesize imidazo[1,2-a]pyridines and imidazo[1,2,3-ij][1,8] naphthyridine derivatives incorporating medicinally privileged heterosystems from heterocyclic ketene aminals, aldehydes, diketene, and amines via cascade reactions, including diketene ring-opening, Knoevenagel condensation, aza-ene reaction, imine-enamine tautomerization, cyclocondensation, and intramolecular S_NAr. This strategy can provide an alternative approach for easy access to the highly substituted imidazo[1,2-a]pyridine derivatives in moderate to good yields using four simple and readily available building blocks under mild conditions. Importantly, the unusual splitting peaks in the ¹H NMR spectra of the products derived from heterocyclic ketene aminals with an o-halogen atom on the aryl ring were explained reasonably by varying the temperature in NMR analysis.

Full text of DOI:10.1021/jo3013836

Article
pubs.acs.org/joc
Four-Component Cascade Heteroannulation of Heterocyclic Ketene
Aminals: Synthesis of Functionalized
Tetrahydroimidazo[1,2‑a]pyridine Derivatives
Ming Li,* Peng Shao, Shu-Wen Wang, Wei Kong, and Li-Rong Wen*
State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of
Science and Technology, Qingdao 266042, People's Republic of China
S
* Supporting Information
ABSTRACT: An efficient and straightforward four-component synthetic protocol has been developed to synthesize
imidazo[1,2-a]pyridines and imidazo[1,2,3-ij][1,8]naphthyridine derivatives incorporating medicinally privileged heterosystems
from heterocyclic ketene aminals, aldehydes, diketene, and amines via cascade reactions, including diketene ring-opening,
Knoevenagel condensation, aza−ene reaction, imine−enamine tautomerization, cyclocondensation, and intramolecular SNAr.
This strategy can provide an alternative approach for easy access to the highly substituted imidazo[1,2-a]pyridine derivatives in
moderate to good yields using four simple and readily available building blocks under mild conditions. Importantly, the unusual
splitting peaks in the 1H NMR spectra of the products derived from heterocyclic ketene aminals with an o-halogen atom on the
aryl ring were explained reasonably by varying the temperature in NMR analysis.
multicomponent cascade reaction from simple and readily
available materials to generate complex molecular architectures
is significant and attractive, especially for the synthesis of
privileged heterocyclic scaffolds.13
INTRODUCTION
■
The imidazo[1,2-a]pyridine nucleus is an important privileged
heterocyclic scaffold in numerous biologically active pharma-
cophores. For example, there this scaffold exists in prominent
anxiolytic drugs such as alpidem (I)1 and necopidem (II),2
PI3KR inhibitors (III),3 inhibitors of TNF-α expression in T
cells (IV),4 allosteric modulators of the metabotropic glutamate
2 (mGlu2) receptor (V),5 and insecticide against pea aphids
(VI) (Figure 1).6 In addition, the imidazo[1,2-a]pyridines show
antibacterial,7 anti-inflammatory and analgesic,8 and hypnose-
lective and anxioselective9 activities. Although a variety of
methodologies and protocols have been reported by a number
of organic or pharmaceutical chemists,10 the preparation of
some specific substituted patterns remains difficult. It is of great
importance to explore a novel and efficient synthetic method to
meet increasing scientific and practical demands.
Carbon−carbon and carbon−heteroatom bond-forming
reactions are central to organic synthesis. The rich and
fascinating chemistry that stems from multicomponent
reactions (MCRs) provides a robust approach for the synthesis
of diverse and complex “druglike” heterocyclic compounds.11
MCRs are important for generating high levels of diversity,
giving rise to complex structures by simultaneous formation of
two or more bonds from simple substrates.12 The design of a
Heterocyclic ketene aminals (HKAs),14 which show
structural features with general formulas A and B (Figure 2),
have proven to be important synthons in organic synthesis.
Reactions of cyclic ketene aminals with a variety of
biselectrophilic groups have so far been applied to construct
five- and six-membered and fused heterocycles during the past
few years.15 Meanwhile, diketene as a strained molecule, which
is readily ring-opened to react with an amine in situ at room
temperature, has been explored as a versatile synthetic building
block for the construction of N-heterocyclic compounds in a
number of new diketene-based reactions.16
In continuation of our research interests regarding the
development of the synthetic utility of HKAs17 and on the basis
of our previous endeavors in exploring novel and practical
MCRs to synthesize useful heterocyclic compounds,18 we
report herein a simple and convenient protocol by extensive use
of aza−ene reaction for synthesis of imidazo[1,2-a]pyridine
Received: July 2, 2012
© XXXX American Chemical Society
A
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Figure 1. Selected examples of imidazo[1,2-a]pyridines with biological and medicinal activities.
yield of 73% (Table 1, entry 3). Then other organic bases such
as DBU, DABCO, DMAP, and piperidine and inorganic bases
such as K2CO3 and KOH were employed as the catalyst to
improve the yield of 5a. However, compared to Et3N, they gave
relatively lower yields (Table 1, entries 4−9). Next the amount
of Et3N was investigated, and the results showed that increasing
or decreasing the amount of Et3N resulted in slightly lower
yields (Table 1, entries 10 and 11). The utility of other
solvents, such as CH3OH, EtOH, CH2Cl2, and DMF, was
unsatisfactory (Table 1, entries 12−15). The solvent-free
condition was also attempted to improve the yield. However,
with no catalyst or with Et3N as the catalyst, the reactions did
not give satisfactory yields (Table 1, entries 16 and 17).
Therefore, it could be concluded that the best reaction
conditions for the preparation of 5a were 0.5 equiv of Et3N
as the catalyst in refluxing MeCN (bold in the table).
Figure 2. Functionalized heterocyclic ketene aminals.
derivatives via a four-component reaction involving the
assembly of the scaffold from [3 + 2 + 1] atom fragments
(Scheme 1). In this four-component domino process, at least
Scheme 1. Retrosynthesis Analysis of Imidazo[1,2-
a]pyridines
To further demonstrate the scope and versatility of this
procedure for the synthesis of tetrahydroimidazo[1,2-a]-
pyridines 5, seven HKAs (1a−g), ten aromatic aldehydes
(2a−j), and seven amines (4a−g) were employed to react with
3 under the optimized conditions (Table 2). As can be seen
from Table 2, all reactions proceeded well and gave rise to the
corresponding products 5 as a racemic mixture. For precursors
1, the larger the number of electron-withdrawing groups on the
aryl ring, the higher the yields of products 5 (Table 2, entries 20
and 21). For precursors 2, the aldehydes with an electron-
withdrawing group on the aryl ring gave higher yields than
those with an electron-donating group (Table 2, entries 23−
27). For both precursors 1 and 2, however, the positions of
substituents on the aryl ring had almost no effect on the yields
of products 5, except a large group at the ortho position in
aromatic aldehydes due to steric hindrance (Table 2, entry 8).
For precursors 4, both the aliphatic amines and the aromatic
amines with a para-electron-donor group such as a methyl
group as well as aniline could afford good yields (Table 2,
entries 3, 11, 12, and 16), while the aromatic amines with a
para-electron-withdrawing group such as a bromo group only
gave moderate yields (Table 2, entry 14). However,
interestingly, the aromatic amines with an ortho-electron-
donor group such as a methyl group or an ortho-electron-
withdrawing group such as a bromo group could decrease the
reactivity, which should be subject to steric hindrance (Table 2,
entries 13 and 15). Unfortunately, we did not obtain the
expected products when aliphatic aldehydes such as n-
butyraldehyde, heteroaromatic aldehydes such as furan-2-
nine chemically distinct reactive sites participated in the
chemical transformation that led to the concomitant creation
of four new bonds (two C−C bonds and two C−N bonds) and
one new ring was generated. So far, to the best of our
knowledge, this is the first protocol for the four-component
reaction (4CR) for the synthetic application of HKAs to
synthesize novel imidazo[1,2-a]pyridine and imidazo[1,2,3-
ij][1,8]naphthyridine derivatives.
RESULTS AND DISCUSSION
■
In the initial experiment, we explored the optimum conditions
for the four-component reaction to synthesize 8-benzoyl-5-
methyl-N,7-diphenyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-
6-carboxamide (5a) by using 2-(imidazolidin-2-ylidene)-1-
phenylethanone (1a), benzaldehyde (2a), diketene (3), and
phenylamine (4a) as model substrates. The effects of different
catalysts, solvents, and temperatures on the yields of the model
reaction were examined (Table 1). Obviously, without any
catalyst, the reaction did not take place at room temperature,
even in refluxing acetonitrile (Table 1, entries 1 and 2). When
Et3N (0.5 equiv) was added, the reaction proceeded smoothly
in refluxing MeCN to give the corresponding product 5a in a
B
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a
Table 1. Optimization of Reaction Conditions for the Synthesis of 5a
b
entry
catalyst (concn/mmol %)
solvent
temp/°C
yield /%
1
2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3OH
EtOH
rt
NR
NR
73
38
41
36
39
35
32
65
70
30
39
27
36
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
100
3
Et3N (0.5)
DBU (0.5)
DABCO (0.5)
DMAP (0.5)
piperidine (0.5)
K2CO3 (0.5)
KOH (0.5)
Et3N (0.3)
Et3N (0.7)
Et3N (0.5)
Et3N (0.5)
Et3N (0.5)
Et3N (0.5)
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CH2Cl2
DMF
c
70
20
c
Et3N (0.5)
70
42
a
b
Reactions were carried out using 1a (1.0 mmol), 2a (1.0 mmol), 3 (1.0 mmol), 4a (1.0 mmol), base, and solvent (5 mL) for 18 h. Isolated yield.
c
Reaction time 3 h.
carbaldehyde, and long-chain aliphatic amines such as lauryl-
amine were used, which can be ascribed to self-condensation of
aliphatic aldehydes and low activity of the heteroaromatic
aldehydes and long-chain aliphatic amines under these reaction
conditions.
three single peaks due to these hydrogen atoms in individual
average environments resulting from rapid rotation of the aryl
ring at high temperature. It was testified fully that the splitting
peaks arose from the rotational barrier contributed by the o-
chlorine atom.
In view of the significance of naphthyridine derivatives,19 we
attempted to use compounds 5s−5cc as the substrates to
prepare benzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbox-
amide derivatives. To our delight, we directly used 5t in the
presence of K2CO3 in DMF at 100 °C to obtain benzo[b]-
imidazo[1,2,3-ij][1,8]naphthyridine-5-carboxamide (6a) in an
excellent yield of 91%.
The structures of the products 5 were identified by their IR,
1H NMR, 13C NMR, and HRMS spectral data and
unequivocally confirmed by X-ray diffraction analysis of a
monocrystal of 5cc (Figure S2 in the Supporting Information).
It is worth mentioning that, in the 1H NMR spectra of
compounds 5s−5cc with a chlorine atom at the ortho position
on the aromatic ring from heterocyclic ketene aminals 1 (Table
2, entries 19−29), there exist three sets of unusual splitting
peaks. Take the compound 5cc, for example (Figure S2,
bottom, in the Supporting Information). For the signal of the
chiral *CH (δ 4.5), an expected singlet appeared as a doublet.
The same phenomenon could also be observed at δ 6.4, which
was the signal of the aryl group with an o-chlorine group, and at
δ 9.6, which was attributed to the NH of the imidazole ring. For
compounds 5a−r without an o-chlorine atom on the aryl ring,
however, this phenomenon did not occur. Therefore, it is
necessary to identify the factors that lead to this phenomenon.
From the crystallographic data of compound 5cc, a strong
intramolecular O(1)···H−N(1) hydrogen bond was observed,
which restricted the free rotation of the carbonyl group. We
reasoned that this result could lead to two isomers due to the
steric hindrance of the o-chlorine atom (Figure 3).
The synthesis of tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]-
naphthyridines 6 does not necessarily require the isolation of
intermediates 5. We conducted the preparation of 6a simply by
stirring the mixture of 1-(2,4-dichloro-5-fluorophenyl)-2-
(imidazolidin-2-ylidene)ethanone (1e), 4-chlorobenzaldehyde
(2c), diketene (3), and phenylamine (4a) in refluxing MeCN
with 0.5 equiv of Et3N as the catalyst for 18 h to give the
expected 5t, followed by, after removal of the solvent, stirring
the residue with 1 equiv of K2CO3 in DMF at 100 °C for about
10 h. The one-pot, two-step process successfully led to the
corresponding product 6a in a good total yield of 81% (Table 3,
entry 1).
Inspired by the above results, the reactions of four HKAs
(1d−f and 1g), six aromatic aldehydes with diketene (3) and
phenylamine (4a) were investigated under the above conditions
(Table 3). The desired products 6 were obtained except 6i,
which may be ascribed to the low activity of the o-halogen
leaving group of the aryl ring without other electron-
withdrawing groups. Thus, a stronger base NaH (1 equiv)
was chosen as the catalyst for 6i. To our delight, the reaction
To verify this inference, we examined the 1H NMR spectrum
of compound 5cc in DMSO-d6 at a higher temperature of 60
°C (Figure S2, top, in the Supporting Information). As
1
expected, in the H NMR spectra of 5cc at 60 °C, the three
original sets of splitting peaks disappeared and were replaced by
C
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a
Table 2. One-Pot Four-Component Synthesis of Products 5
D
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Table 2. continued
E
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Table 2. continued
F
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Table 2. continued
a
b
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol), 4 (1.0 mmol), Et3N (0.5 equiv), refluxing MeCN (5 mL), 18 h. Isolated yield.
c
Reation time 30 h.
CONCLUSION
■
In summary, we have developed a convenient, efficient
synthetic protocol for imidazo[1,2-a]pyridines and imidazo-
[1,2,3-ij][1,8]naphthyridines by four-component domino re-
actions of HKAs, aldehydes, diketene, and amines using Et3N as
the catalyst. The transformation involving multiple steps and
not requiring the use of transition-metal catalysts constructs at
least four new bonds with all reactants efficiently being utilized.
Figure 3. Isomerization results from the rotational barrier.
These studies highlighted the concept of a substrate-design
approach and paved an efficient and flexible way to synthesize
biologically active imidazo[1,2-a]pyridine and imidazo[3,2,1-
ij][1,8]naphthyridines with structural diversity. Importantly, the
unusual splitting peaks in the 1H NMR spectra of the products
derived from heterocyclic ketene aminals with an o-halogen
atom on the aryl ring were explained reasonably by varying the
temperature in NMR analysis. We hope this approach may be
of value for other researchers to seek novel synthetic fragments
with unique properties for medicinal chemistry.
proceeded smoothly, and 6i was gained in a yield of 65%
(Table 3, entry 9).
The structures of 6a−i were characterized by their IR, NMR,
and HRMS spectral data, which are in agreement with the
proposed structures. It is worth noting that in all of the H
NMR spectra of products 6 there is one set of signals with no
1
unusual splitting peaks, which also further demonstrated the
1
splitting peaks in the H NMR spectra of products 5s−5cc
arising from the rotational barrier involving the o-chlorine
atom.
EXPERIMENTAL SECTION
■
General Procedure for the Preparation of Products 5. A
solution of diketene (3; 1.0 mmol) and amines 4 (1.0 mmol) was
stirred in dry MeCN (5 mL) at room temperature with Et3N (0.5
mmol) as the catalyst for 10 min. Then heterocyclic ketene aminals 1
(1.0 mmol) and aromatic aldehydes 2 (1.0 mmol) were added, and the
mixture was heated to reflux for 18 h. After completion of the reaction
as indicated by TLC (petroleum ether−EtOAc, 1:4, v/v), the solvent
was removed under vacuum, and the residue was purified by column
chromatography (petroleum ether−EtOAc, 1:4, v/v) to afford
products 5.
On the basis of the above results, a plausible mechanism for
this reaction was proposed (Scheme 2). First, the attack on the
carbonyl group of diketene (3) by the amino moiety 4 led to
the carboanion [A] under Et3N as the catalyst. Then [A]
underwent Knoevenagel condensation with 2 to give [B]. Next
the heterocyclic ketene aminals 1, as aza−ene reaction
components, reacted with intermediates [B] to afford
intermediates [C], which underwent a rapid imine−enamine
tautomerization to give intermediates [D]. Then an intra-
molecular cyclization of [D] led to the formation of
imidazo[1,2-a]pyridines 5 with loss of one molecule of H2O.
Finally, the carbon attached to the o-chlorine on the aryl group
of compounds 5 was attacked by the NH group through SNAr,
leading to the benzo[b]imidazo[1,2,3-ij][1,8]naphthyridine
derivatives 6 with elimination of HCl.
General Procedure for the Preparation of Products 6. A
solution of diketene (3; 1.0 mmol) and phenylamine (4a; 1.0 mmol)
was stirred in dry MeCN (5 mL) at room temperature with Et3N (0.5
mmol) as the catalyst for 10 min. Then heterocyclic ketene aminals 1
(1.0 mmol) and aromatic aldehydes 2 (1.0 mmol) were added, and the
mixture was heated to reflux for 18 h. After completion of the reaction
as indicated by TLC (petroleum ether−EtOAc, 1:4, v/v), the solvent
G
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a
Table 3. Synthesis of Products 6 via Tandem Reaction
a
Reaction conditions: (i) 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol), 4 (1.0 mmol), Et3N (0.5 equiv), refluxing MeCN (5 mL), 18 h; (ii) K2CO3 (1
b
c
equiv), DMF (5 mL), 100 °C, 10 h. Total isolated yield of 6 based on 1. Reaction conditions: NaH (1 equiv), DMF (5 mL), 100 °C, 10 h.
was removed under vacuum. To the residue were added DMF (5 mL)
and K2CO3 (1 mmol), and the resulting mixture was then heated to
100 °C for 10 h. After completion of the reaction as indicated by TLC
(petroleum ether−EtOAc, 1:6, v/v), the mixture was cooled to room
temperature. Ice−water was added to precipitate the products, which
were then filtered and washed with ethanol to give pure products 6.
Data for 8-benzoyl-5-methyl-N,7-diphenyl-1,2,3,7-
tetrahydroimidazo[1,2-a]pyridine-6-carboxamide (5a): isolated
yield 318 mg (73%); brown powder; mp 243−245 °C; IR (KBr) ν
Data for 8-benzoyl-7-(4-fluorophenyl)-5-methyl-N-phenyl-
1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxamide (5b):
isolated yield 385 mg (85%); yellow powder; mp 229−231 °C; IR
(KBr) ν 3289, 1660, 1635, 1599, 1504, 1484, 1440, 1289, 1248, 852,
1
755, 703 cm−1; H NMR (CDCl3, 500 MHz) δ 2.32 (s, 3H), 3.82−
3.99 (m, 4H), 4.73 (s, 1H), 6.64−7.33 (m, 15H), 9.26 (s, 1H); 13C
NMR (CDCl3, 125 MHz) δ 16.3, 41.9, 42.6, 45.0, 88.7, 112.4, 115.5
(2JC−F = 21.1 Hz), 119.6, 124.1, 126.4, 128.3, 128.6, 128.7, 128.9,
137.8, 138.0, 141.8, 142.7, 142.2, 156.4, 161.6 (1JC−F = 244.4 Hz),
166.8, 192.9; HRMS (ESI-TOF, [M + H]+) m/z calcd for
C28H25N3O2F 454.1931, found 454.1941.
1
3272, 1663, 1634, 1598, 1488, 1439, 1289, 1248, 755, 699 cm−1; H
NMR (CDCl3, 500 MHz) δ 2.35 (s, 3H), 3.82−4.02 (m, 4H), 4.71 (s,
1H), 6.69−7.34 (m, 16H), 9.27 (s, 1H); 13C NMR (CDCl3, 125
MHz) δ 16.3, 42.5, 42.6, 45.0, 88.8, 112.1, 112.2, 119.5, 123.9, 126.6,
127.1, 128.2, 128.2, 128.8, 138.0, 138.6, 138.9, 141.9, 146.8, 156.4,
166.8, 192.9; HRMS (ESI-TOF, [M + H]+) m/z calcd for
C28H26N3O2 436.2025, found 436.2032.
Data for 8-benzoyl-7-(4-chlorophenyl)-5-methyl-N-phenyl-
1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxamide (5c):
isolated yield 375 mg (80%); light yellow powder; mp 247−249 °C;
IR (KBr) ν 3307, 1660, 1600, 1486, 1438, 1289, 1244, 833, 753, 702
1
cm−1; H NMR (CDCl3, 500 MHz) δ 2.30 (s, 3H), 3.81−3.99 (m,
4H), 4.72 (s, 1H), 6.62−7.34 (m, 15H), 9.26 (s, 1H); 13C NMR
H
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Scheme 2. Plausable Mechanism for the Formation of Compounds 5 and 6
(CDCl3, 125 MHz) δ 16.3, 42.0, 42.7, 45.0, 88.3, 112.2, 119.7, 124.2,
126.4, 128.3, 128.4, 128.8, 128.9, 132.5, 137.8, 138.0, 141.7, 145.3,
156.4, 166.8, 192.8; HRMS (ESI-TOF, [M + H]+) m/z calcd for
C28H25N3O2Cl 470.1635, found 470.1645.
Data for 8-benzoyl-7-(4-bromophenyl)-5-methyl-N-phenyl-
1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxamide (5d):
isolated yield 390 mg (76%); yellow powder; mp 246−248 °C; IR
(KBr) ν 3286, 1655, 1660, 1599, 1482, 1437, 1288, 1248, 832, 753,
702 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.29 (s, 3H), 3.80−3.98 (m,
4H), 4.72(s, 1H), 6.57−7.34 (m, 15H), 9.27 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 16.2, 42.2, 42.6, 45.0, 88.2, 112.3, 119.7, 120.6,
124.2, 126.4, 128.3, 128.8, 128.9, 131.7, 137.7, 137.8, 141.8, 145.8,
156.5, 166.8, 192.8; HRMS (ESI-TOF, [M + H]+) m/z calcd for
C28H25N3O2Br 514.1130, found 514.1125.
isolated yield 385 mg (82%); light yellow powder; mp 239−241 °C;
IR (KBr) ν 3289, 1667, 1655, 1600, 1487, 1439, 1289, 1251, 753, 702
1
cm−1; H NMR (CDCl3, 500 MHz) δ 2.25 (s, 3H), 3.86−4.02 (m,
4H), 5.22 (s, 1H), 6.83−7.29 (m, 15H), 9.38 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 16.4, 40.1, 42.9, 45.2, 88.1, 112.5, 120.2, 124.4,
126.3, 127.6, 128.1, 128.5, 128.8, 129.0, 129.8, 131.1, 132.3, 136.3,
138.1, 142.2, 144.3, 157.2, 166.9, 193.6; HRMS (ESI-TOF, [M + H]+)
m/z calcd for C28H25N3O2Cl 470.1635, found 470.1625.
Data for 8-benzoyl-7-(3-chlorophenyl)-5-methyl-N-phenyl-
1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxamide (5j):
isolated yield 380 mg (81%); white powder; mp 220−222 °C; IR
(KBr) ν 3305, 1663, 1637, 1598, 1482, 1439, 1289, 1248, 754, 702
1
cm−1; H NMR (CDCl3, 500 MHz) δ 2.33 (s, 3H), 3.84−4.02 (m,
4H), 4.74 (s, 1H), 6.51−7.37 (m, 15H), 9.30 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 16.6, 42.7, 42.9, 45.3, 88.4, 112.2, 119.9, 124.4,
125.5, 126.6, 127.3, 127.6, 128.5, 129.1, 130.1, 134.8, 138.0, 138.3,
141.9, 149.0, 156.6, 166.9, 193.1; HRMS (ESI-TOF, [M + H]+) m/z
calcd for C28H25N3O2Cl 470.1635, found 470.1642.
Data for 8-benzoyl-5-methyl-7-(4-nitrophenyl)-N-phenyl-
1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxamide (5e):
isolated yield 403 mg (84%); yellow powder; mp 201−203 °C; IR
(KBr) ν 3291, 3288, 1663, 1651, 1604, 1510, 1438, 1290, 1251, 813,
1
753, 699 cm−1; H NMR (CDCl3, 500 MHz) δ 2.23 (s, 3H), 3.79−
Data for 8-benzoyl-N-benzyl-7-(4-chlorophenyl)-5-methyl-
1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxamide (5k):
isolated yield 416 mg (86%); white powder; mp 231−233 °C; IR
(KBr) ν 3274, 1667, 1619, 1608, 1487, 1453, 1286, 1257, 754, 705
3.94 (m, 4H), 4.96 (s, 1H), 6.87−7.95 (m, 15H), 9.25 (s, 1H); 13C
NMR (CDCl3, 125 MHz) δ 16.2, 42.7, 42.9, 44.9, 87.3, 112.6, 119.9,
123.6, 124.4, 126.2, 127.9, 128.3, 129.0, 136.0, 137.6, 141.6, 146.4,
154.2, 156.7, 166.7, 192.5; HRMS (ESI-TOF, [M + H]+) m/z calcd
for C28H25N4O4 481.1876, found 481.1889.
1
cm−1; H NMR (CDCl3, 500 MHz) δ 2.23 (s, 3H), 3.79−3.93 (m,
4H), 4.12−4.46 (m, 2H), 4.73 (s, 1H), 5.30 (s, 1H), 6.52−7.33 (m,
14H), 9.22 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 16.1, 42.3, 42.7,
43.5, 45.0, 88.2, 112.9, 126.4, 127.3, 128.2, 128.5, 128.6, 128.7, 132.1,
135.3, 138.0, 141.9, 145.46, 156.7, 168.6, 192.9; HRMS (ESI-TOF, [M
+ H]+) m/z calcd for C29H27N3O2Cl 484.1792, found 484.1796.
Data for 8-benzoyl-7-(4-chlorophenyl)-5-methyl-N-(p-tolyl)-
1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxamide (5l):
isolated yield 372 mg (77%); gray powder; mp 235−237 °C; IR
(KBr) ν 3285, 1664, 1632, 1605, 1487, 1452, 1287, 1250, 815, 752,
705 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.26 (s, 3H), 2.30 (s, 3H),
3.84−3.99 (m, 4H), 4.71 (s, 1H), 6.62−7.33 (m, 14H), 9.27 (s, 1H);
13C NMR (CDCl3, 125 MHz) δ 16.3, 20.9, 42.1, 42.7, 45.1, 88.4,
Data for 8-benzoyl-5-methyl-N-phenyl-7-(p-tolyl)-1,2,3,7-
tetrahydroimidazo[1,2-a] pyridine-6-carboxamide (5f): isolated
yield 274 mg (61%); light brown powder; mp 237−239 °C; IR (KBr)
ν 3293, 1667, 1637, 1598, 1487, 1439, 1290, 1249, 838, 755, 704 cm−1;
1H NMR (CDCl3, 500 MHz) δ 2.27 (s, 3H), 2.35 (s, 3H), 3.80−4.03
(m, 4H), 4.66 (s, 1H), 6.56−7.36 (m, 15H), 9.22 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 16.3, 21.0, 42.0, 42.6, 45.0, 89.0, 112.1, 119.5,
123.8, 126.7, 126.9, 128.2, 128.8, 129.5, 136.6, 138.2, 139.0, 141.9,
143.8, 156.4, 166.9, 192.8; HRMS (ESI-TOF, [M + H]+) m/z calcd
for C29H28N3O2 450.2182, found 450.2172.
Data for 8-benzoyl-7-(4-methoxyphenyl)-5-methyl-N-phe-
nyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxamide
(5g): isolated yield 256 mg (55%); brown powder; mp 229−231 °C;
IR (KBr) ν 3279, 1660, 1632, 1605, 1508, 1485, 1439, 1289, 1244,
829, 754, 706 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.37 (s, 3H), 3.76
(s, 3H), 3.83−4.05 (m, 4H), 4.66 (s, 1H), 6.61−7.36 (m, 15H), 9.25
(s, 1H); 13C NMR (CDCl3, 125 MHz) δ 16.3, 41.6, 42.6, 45.1, 55.2,
89.2, 112.2, 114.2, 119.5, 123.8, 126.6, 128.2, 128.8, 138.1, 138.9,
139.1, 141.9, 156.3, 158.6, 166.9, 192.9; HRMS (ESI-TOF, [M + H]+)
m/z calcd for C29H28N3O3 466.2131, found 466.2138.
112.5, 119.8, 126.5, 128.3, 128.5, 128.8, 128.9, 129.4, 132.5, 133.9,
135.2, 137.6, 141.8, 145.4, 156.6, 166.8, 192.9; HRMS (ESI-TOF, [M
+ H]+) m/z calcd for C29H27N3O2Cl 484.1792, found 484.1786.
Data for 8-benzoyl-N-(4-bromophenyl)-7-(4-chlorophenyl)-
5-methyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxa-
mide (5n): isolated yield 280 mg (51%); yellow powder; mp 245−247
°C; IR (KBr) ν 3270, 1670, 1606, 1486, 1455, 1285, 1248, 796, 750,
704 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.30 (s, 3H), 3.83−3.99 (m,
4H), 4.70 (s, 1H), 6.60−7.36 (m, 14H), 9.23 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 16.4, 42.0, 42.7, 45.0, 88.3, 111.7, 116.6, 121.2,
126.4, 128.3, 128.4, 128.9, 129.0, 131.8, 132.6, 136.9, 138.6, 141.7,
Data for 8-benzoyl-7-(2-chlorophenyl)-5-methyl-N-phenyl-
1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxamide (5i):
I
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145.2, 156.3, 166.7, 192.8; HRMS (ESI-TOF, [M + H]+) m/z calcd
for C28H24N3O2BrCl 548.0740, found 548.0749.
1H); 13C NMR (CDCl3, 125 MHz) δ 16.2, 42.2, 42.8, 45.0, 88.9,
113.5, 119.7, 124.3, 127.1, 127.7, 128.7, 129.0, 129.8, 130.2, 132.7,
134.5, 136.0, 137.6, 145.3, 156.8, 166.7, 187.9; HRMS (ESI-TOF, [M
+ H]+) m/z calcd for C28H23N3O2Cl3 538.0856, found 538.0867.
Data for 8-(2,5-dichlorobenzoyl)-5-methyl-N,7-diphenyl-
1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxamide (5v):
isolated yield 407 mg (81%); light yellow powder; mp 221−223 °C;
IR (KBr) ν 3277, 1688, 1652, 1600, 1440, 1289, 1253, 823, 754, 696
Data for 8-benzoyl-N-(2-bromophenyl)-7-(4-chlorophenyl)-
5-methyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxa-
mide (5o): isolated yield 165 mg (30%); yellowgreen powder; mp
145−147 °C; IR (KBr) ν 3417, 1672, 1631, 1518, 1479, 1452, 1290,
1
1244, 795, 749, 704 cm−1; H NMR (CDCl3, 500 MHz) δ 2.40 (s,
3H), 3.83−4.04 (m, 4H), 4.87 (s, 1H), 6.65−8.20 (m, 14H), 9.23 (s,
1H); 13C NMR (CDCl3, 125 MHz) δ 16.4, 41.7, 42.7, 45.1, 88.4,
111.7, 113.7, 122.4, 125.0, 126.7, 128.1, 128.3, 128.3, 128.8, 129.0,
132.1, 132.4, 135.8, 139.3, 141.6, 144.6, 156.4, 166.5, 192.6; HRMS
(ESI-TOF, [M + H]+) m/z calcd for C28H24N3O2BrCl 548.0740,
found 548.0736.
1
cm−1; H NMR (CDCl3, 500 MHz) δ 2.25 (s, 3H), 3.85−4.03 (m,
4H), 4.28 (s, 1H), 6.39−7.29 (m, 14H), 9.35 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 16.4, 42.8, 45.1, 89.5, 113.6, 119.7, 124.1, 127.5,
129.0, 129.5, 130.5, 132.6, 136.4, 137.9, 142.1, 146.9, 156.9, 166.9,
187.5; HRMS (ESI-TOF, [M + H]+) m/z calcd for C28H24N3O2Cl2
504.1246, found, 504.1256.
Data for 8-(2,5-dichlorobenzoyl)-7-(4-fluorophenyl)-5-meth-
yl-N-phenyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-car-
boxamide (5w): isolated yield 495 mg (95%); green powder; mp
236−238 °C; IR (KBr) ν 3277, 1671, 1652, 1600, 1505, 1491, 1441,
1290, 1254, 795, 756, 693 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.20
(s, 3H, CH3), 3.84−3.99 (m, 4H), 4.33 (s, 1H), 6.39−7.26 (m, 13H,),
9.32 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 16.3, 42.0, 42.8, 45.1,
89.2, 113.8, 115.5 (2JC−F = 21.1 Hz), 119.7, 124.3, 126.7, 127.3, 129.0,
130.5, 132.6, 135.5, 137.7, 142.0, 142.8, 156.9, 161.8 (1JC−F = 244.8
Hz), 166.8, 187.5; HRMS (ESI-TOF, [M + H]+) m/z calcd for
C28H23N3O2Cl2F 522.1151, found, 522.1162.
Data for 7-(4-chlorophenyl)-8-(2,5-dichlorobenzoyl)-5-
methyl-N-phenyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-
carboxamide (5x): isolated yield 456 mg (85%); light green powder;
mp 211−213 °C; IR (KBr) ν 3258, 1668, 1636, 1595, 1483, 1440,
1290, 1258, 819, 754, 691 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.21
(s, 3H), 3.85−4.00 (m, 4H), 4.34 (s, 1H), 6.40−7.27 (m, 13H), 9.33
(s, 1H); 13C NMR (CDCl3, 125 MHz) δ 16.1, 42.3, 42.8, 45.0, 88.8,
113.7, 119.8, 124.3, 127.2, 128.7, 128.9, 129.2, 130.4, 132.6, 132.8,
135.2, 137.6, 141.9, 145.4, 156.9, 166.7, 187.5; HRMS (ESI-TOF, [M
+ H]+) m/z calcd for C28H23N3O2Cl3 538.0856, found 538.0862.
Data for 7-(4-bromophenyl)-8-(2,5-dichlorobenzoyl)-5-
methyl-N-phenyl-1,2,3,7- tetrahydroimidazo[1,2-a]pyridine-6-
carboxamide (5y): isolated yield 471 mg (81%); light yellow
powder; mp 224−236 °C; IR (KBr) ν 3277, 1668, 1636, 1596, 1483,
1439, 1290, 1252, 819, 754, 692 cm−1; 1H NMR (CDCl3, 500 MHz) δ
2.21 (s, 3H), 3.86−4.01 (m, 4H), 4.33 (s, 1H), 6.40−7.29 (m, 13H),
9.33 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 16.2, 42.2, 42.8, 45.0,
88.8, 113.6, 119.7, 120.8, 124.3, 127.2, 129.0, 129.2, 130.4, 131.7,
132.7, 135.3, 137.6, 141.8, 145.9, 156.9, 166.7, 187.4; HRMS (ESI-
TOF, [M + H]+) m/z calcd for C28H23N3O2Cl2Br 582.0351, found
582.0358.
Data for 8-benzoyl-7-(4-chlorophenyl)-N-cyclohexyl-5-
methyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxa-
mide (5p): isolated yield 380 mg (80%); brown powder; mp 243−245
°C; IR (KBr) ν 3270, 2931, 2854, 1667, 1615, 1487, 1452, 1287, 1253,
1
798, 751, 704 cm−1; H NMR (CDCl3, 500 MHz) δ 0.73−1.72 (m,
10H), 2.17 (s, 3H), 3.62−3.68 (m, 1H), 3.84−3.95 (m, 4H), 4.64 (s,
1H), 4.85 (d, J = 8 Hz, 1H), 6.58−7.32 (m, 10H), 9.26 (s, 1H); 13C
NMR (CDCl3, 125 MHz) δ 15.9, 24.5, 25.4, 32.7, 42.4, 42.6, 45.0,
48.0, 88.1, 113.6, 126.4, 128.2, 128.4, 128.6, 128.7, 132.0, 133.8, 141.9,
145.6, 156.8, 167.9, 192.9; HRMS (ESI-TOF, [M + H]+) m/z calcd
for C28H31N3O2Cl, 476.2105 found 476.2115.
Data for 8-(4-chlorobenzoyl)-7-(4-chlorophenyl)-5-methyl-
N-phenyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxa-
mide (5q): isolated yield 392 mg (78%); yellow powder; mp 165−167
°C; IR (KBr) ν 1667, 1637, 1597, 1486, 1440, 1289, 1252, 757, 693
1
cm−1; H NMR (CDCl3, 500 MHz) δ 2.30 (s, 3H), 3.86−4.01 (m,
4H), 4.66(s, 1H), 6.68−7.28 (m, 14H), 9.27 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 16.3, 42.2, 42.7, 45.1, 88.2, 112.6, 119.8, 124.3,
128.0, 128.4, 128.5, 129.0, 132.8, 134.8, 137.3, 137.7, 140.2, 145.3,
156.7, 166.7, 191.4; HRMS (ESI-TOF, [M + H]+) m/z calcd for
C28H24N3O2Cl2 504.1246, found 504.1256.
Data for 8-(3-chlorobenzoyl)-7-(4-chlorophenyl)-5-methyl-
N-phenyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxa-
mide (5r): isolated yield 402 mg (80%); yellow powder; mp 150−152
°C; IR (KBr) ν 3282, 1667, 1637, 1596, 1485, 1439, 1289, 1251, 757,
692 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.30 (s, 3H), 3.84−4.03 (m,
4H), 4.66 (m, 1H), 6.68−7.28 (m, 14H), 9.28 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 16.2, 42.1, 42.7, 45.1, 88.2, 112.7, 119.8, 124.3,
128.0, 128.4, 128.5, 129.0, 132.7, 134.8, 137.1, 137.7, 140.1, 145.2,
156.7, 166.7, 191.3; HRMS (ESI-TOF, [M + H]+) m/z calcd for
C28H24N3O2Cl2 504.1246, found 504.1256.
Data for 8-(2-chlorobenzoyl)-7-(4-chlorophenyl)-5-methyl-
N-phenyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carboxa-
mide (5s): isolated yield 402 mg (80%); brown powder; mp 210−212
°C; IR (KBr) ν 3276, 1665, 1663, 1604, 1488, 1436, 1290, 1254, 838,
Data for 8-(2,5-dichlorobenzoyl)-5-methyl-7-(4-nitrophen-
yl)-N-phenyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-car-
boxamide (5z): isolated yield 504 mg (92%); brown powder; mp
216−218 °C; IR (KBr) ν 3270, 1670, 1630, 1609, 1518, 1488, 1440,
1290, 1243, 821, 763, 700 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.24
(s, 3H), 3.93−4.06 (m, 4H), 4.59 (s, 1H), 6.34−8.01 (m, 13H), 9.40
(s, 1H); 13C NMR (CDCl3, 125 MHz) δ 16.2, 42.9, 45.1, 87.9, 113.6,
119.9, 123.7, 124.7, 127.3, 128.2, 129.1, 129.5, 130.6, 132.8, 134.5,
137.4, 141.8, 146.6, 154.0, 157.0, 166.4, 187.5; HRMS (ESI-TOF, [M
+ H]+) m/z calcd for C28H23N4O4Cl2 549.1096, found 549.1085.
Data for 8-(2,5-dichlorobenzoyl)-7-(4-methoxyphenyl)-5-
methyl-N-phenyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-
carboxamide (5aa): isolated yield 330 mg (62%); white powder; mp
188−190 °C; IR (KBr) ν 3309, 1672, 1632, 1608, 1487, 1440, 1290,
1
755, 694 cm−1; H NMR (CDCl3, 500 MHz) δ 2.24 (s, 3H), 3.85−
3.98 (m, 4H), 4.40 (s, 1H), 6.62−7.35 (m, 14H), 9.32 (s, 1H); 13C
NMR (CDCl3, 125 MHz) δ 16.1, 42.2, 42.8, 45.0, 88.9, 113.3, 119.6,
124.2, 126.8, 128.6, 128.9, 129.2, 129.4, 130.1, 132.4, 136.3, 136.7,
137.8, 140.2, 140.6, 145.3, 156.7, 166.8, 189.2; HRMS (ESI-TOF, [M
+ H]+) m/z calcd for C28H24N3O2Cl2 504.1246, found 504.1241.
Data for 7-(4-chlorophenyl)-8-(2,4-dichloro-5-fluorobenzo-
yl)-5-methyl-N-phenyl-1,2,3,7-tetrahydroimidazo[1,2-a]-
pyridine-6-carboxamide (5t): isolated yield 494 mg (89%); green
powder; mp 186−188 °C; IR (KBr) ν 1667, 1663, 1598, 1488, 1439,
1289, 1254, 836, 756, 722, 693 cm−1; 1H NMR (CDCl3, 500 MHz) δ
2.22 (s, 3H), 3.88−4.03 (m, 4H), 4.37 (s, 1H), 6.30−7.42 (m, 12H),
9.32 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 16.2, 42.3, 42.8, 45.1,
88.6, 113.9, 117.2, 119.8, 121.5 (2JC−F = 19.0 Hz), 124.4, 128.7, 128.8,
129.0 131.1, 132.9, 135.1, 137.6, 140.5, 145.2, 156.6 (1JC−F = 250.0
Hz), 157.1, 166.6, 186.5; HRMS (ESI-TOF, [M + H]+) m/z calcd for
C28H22N3O2Cl3F 556.0762, found 556.0775.
1
1240, 820, 762, 694 cm−1; H NMR (CDCl3, 500 MHz) δ 2.27 (s,
3H), 3.80 (s, 3H), 3.85−4.04 (m, 4H), 4.23 (s, 1H), 6.42−7.30 (m,
13H), 9.35 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 11.6, 37.0, 38.0,
40.4, 50.7, 85.1, 108.9, 109.5, 114.9, 119.3, 123.8, 124.2, 124.4, 124.8,
125.7, 127.8, 133.2, 134.4, 152.0, 154.0, 162.2, 182.8; HRMS (ESI-
TOF, [M + H]+) m/z calcd for C29H26N3O3Cl2 534.1351, found
534.1342.
Data for 7-(2-chlorophenyl)-8-(2,5-dichlorobenzoyl)-5-
methyl-N-phenyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-
carboxamide (5bb): isolated yield 462 mg (86%); yellow powder;
mp 242−244 °C; IR (KBr) ν 3277, 1673, 1662, 1609, 1491, 1440,
Data for 7-(4-chlorophenyl)-8-(2,4-dichlorobenzoyl)-5-
methyl-N-phenyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-
carboxamide (5u): isolated yield 440 mg (82%); gray powder; mp
176−178 °C; IR (KBr) ν 3293, 1667, 1663, 1601, 1486, 1438, 1290,
1
1254, 827, 757, 693 cm−1; H NMR (CDCl3, 500 MHz) δ 2.24 (s,
3H), 3.88−4.03 (m, 4H), 4.39 (s, 1H), 6.51−7.39 (m, 13H), 9.34 (s,
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1289, 1251, 815, 749, 693 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.14
(s, 3H), 3.86−4.00 (m, 4H), 4.95 (s, 1H), 6.18−7.28 (m, 13H), 9.44
(s, 1H); 13C NMR (CDCl3, 125 MHz) δ 16.1, 39.2, 42.8, 45.0, 88.9,
113.2, 120.0, 124.3, 127.0, 127.6, 128.1, 128.4, 128.9, 129.2, 130.5,
130.9, 131.3, 132.6, 134.1, 137.8, 142.1, 144.0, 157.4, 166.4, 187.7;
HRMS (ESI-TOF, [M + H]+) m/z calcd for C28H23N3O2Cl3
538.0856, found 538.0862.
Data for 7-(3-chlorophenyl)-8-(2,5-dichlorobenzoyl)-5-
methyl-N-phenyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-
carboxamide (5cc): isolated yield 446 mg (83%); light green
powder; mp 240−242 °C; IR (KBr) ν 3213, 1667, 1644, 1596, 1495,
1438, 1286, 1254, 829, 747, 700 cm−1; 1H NMR (CDCl3, 500 MHz) δ
2.26 (s, 3H), 3.92−4.05 (m, 4H), 4.35 (s, 1H), 6.42−7.28 (m, 13H),
9.37 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 16.2, 42.8, 45.0, 88.8,
113.4, 119.8, 124.3, 125.5, 127.3, 127.6, 127.9, 129.0, 129.4, 129.8,
130.5, 131.2, 132.7, 134.7, 135.7, 137.6, 142.0, 148.8, 156.8, 166.6;
HRMS (ESI-TOF, [M + H]+) m/z calcd for C28H23N3O2Cl3
538.0856, found 538.0868.
Data for 10-chloro-6-(4-chlorophenyl)-9-fluoro-4-methyl-7-
oxo-N-phenyl-1,2,6,7-tetrahydrobenzo[b]imidazo[1,2,3-ij]-
[1,8]naphthyridine-5-carboxamide (6a): isolated yield 420 mg
(81%); white powder; mp 258−260 °C; IR (KBr, cm−1) 3254, 1672,
1647, 1590, 1521, 1428, 1293, 1233, 766, 753, 694; 1H NMR (DMSO-
d6, 500 MHz) δ 2.18 (s, 3H), 4.15−4.49 (m, 4H), 5.31 (s, 1H), 6.98−
7.76 (m, 11H), 9.82 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 15.8,
45.4, 45.8, 97.6, 112.3 (2JC−F = 24.3 Hz), 117.6, 120.2, 123.7, 125.2,
128.2, 129.0, 130.2, 131.1, 134.4, 135.8, 139.6, 144.8, 148.4, 153.3
(1JC−F = 241.1 Hz), 167.3, 172.2; HRMS (ESI-TOF, [M + H]+) m/z
calcd for C28H21N3O2FCl2 520.0995, found 520.0986.
Data for 9-chloro-6-(4-methoxyphenyl)-4-methyl-7-oxo-N-
phenyl-1,2,6,7-tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]-
naphthyridine-5-carboxamide (6f): isolated yield 298 mg (60%);
light yellow powder; mp 255−257 °C; IR (KBr) ν 3256, 1674, 1651,
1
1595, 1519, 1437, 751, 699 cm−1; H NMR (DMSO-d6, 500 MHz) δ
2.24 (s, 3H), 3.67 (s, 3H), 4.19−4.55 (m, 4H), 5.33 (s, 1H), 6.75−
7.93 (m, 12H), 9.84 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 15.7,
45.4, 55.4, 98.7, 112.9, 113.7, 117.5, 120.2, 123.6, 125.0, 126.6, 127.1,
129.0, 129.3, 131.4, 135.5, 136.0, 138.4, 139.8, 148.1, 158.0, 167.6,
172.4; HRMS (ESI-TOF, [M + H]+) m/z calcd for C29H25N3O3Cl
498.1584, found 498.1573.
Data for 9-chloro-6-(3-chlorophenyl)-4-methyl-7-oxo-N-
phenyl-1,2,6,7-tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]-
naphthyridine-5-carboxamide (6g): isolated yield 346 mg (69%);
light yellow powder; mp 248−250 °C; IR (KBr) ν 3274, 1667, 1616,
1
1596, 1521, 1440, 1253, 1220, 755, 694 cm−1; H NMR (DMSO-d6,
500 MHz) δ 2.20 (s, 3H), 4.14−4.48 (m, 4H), 5.35 (s, 1H), 7.02−7.91
(m, 12H), 9.85 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 15.7, 45.4,
97.6, 111.8, 117.5, 120.3, 123.6, 125.0, 126.4, 127.0, 127.2, 128.0,
128.9, 130.0, 131.5, 133.0, 136.0, 139.6, 148.2, 148.3, 167.2, 172.4;
HRMS (ESI-TOF, [M + H]+) m/z calcd for C28H22N3O2Cl2
502.1089, found 502.1096.
Data for 9-chloro-6-(2-chlorophenyl)-4-methyl-7-oxo-N-
phenyl-1,2,6,7-tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]-
naphthyridine-5-carboxamide (6h): isolated yield 351 mg (70%);
yellow powder; mp 250−252 °C; IR (KBr) ν 3278, 3241, 1668, 1617,
1
1597, 1522, 1440, 1256, 756, 692 cm−1; H NMR (DMSO-d6, 500
MHz) δ 2.10 (s, 3H), 4.09−4.45 (m, 4H), 5.73 (s, 1H), 6.94−7.85 (m,
12H), 9.96 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 15.4, 45.2,
45.5, 98.4, 112.6, 117.5, 120.2, 123.5, 125.0, 126.4, 127.2, 127.5, 128.0,
128.9, 129.2, 131.5, 131.8, 132.6, 134.3, 136.2, 139.8, 143.9, 148.6,
167.0, 172.2; HRMS (ESI-TOF, [M + H]+) m/z calcd for
C28H22N3O2Cl2 502.1089, found 502.1096.
Data for 10-chloro-6-(4-chlorophenyl)-4-methyl-7-oxo-N-
phenyl-1,2,6,7-tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]-
naphthyridine-5-carboxamide (6b): isolated yield 361 mg (72%);
white powder; mp 263−265 °C; IR (KBr) ν 3256, 1668, 1615, 1596,
1
1523, 1436, 1296, 1246, 780, 756, 694 cm−1; H NMR (DMSO-d6,
Data for 6-(4-chlorophenyl)-4-methyl-7-oxo-N-phenyl-
1,2,6,7-tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]-
naphthyridine-5-carboxamide (6i): isolated yield 304 mg (65%);
light yellow powder; mp 257−259 °C; IR (KBr) ν 1666, 1617, 1597,
500 MHz) δ 2.19 (s, 3H), 4.13−4.46 (m, 4H), 5.32 (s, 1H), 7.01−7.94
(m, 12H), 9.88 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 15.8, 21.2,
45.4, 60.2, 79.6, 97.8, 112.2, 114.9, 120.3, 122.7, 123.7, 123.9, 128.0,
128.2, 129.0, 130.2, 131.0, 135.8, 136.5, 138.3, 139.6, 145.0, 148.3,
167.4, 170.9, 173.1; HRMS (ESI-TOF, [M + H]+) m/z calcd for
C28H22N3O2Cl2 502.1089, found 502.1092.
1
1578, 1521, 1249, 756, 693 cm−1; H NMR (DMSO-d6, 500 MHz) δ
2.19 (s, 3H), 4.10−4.45 (m, 2H), 5.35 (s, 1H), 7.00−7.98 (m, 13H),
9.91 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 20.5, 50.0, 50.1,
102.3, 116.8, 119.9, 125.0, 127.2, 128.4, 130.0, 130.7, 132.9, 133.7,
134.9, 135.7, 136.5, 140.7, 142.1, 144.5, 150.0, 152.6, 172.3, 178.5;
HRMS (ESI-TOF, [M + H]+) m/z calcd for C28H23N3O2Cl 468.1479,
found 468.1485.
Data for 9-chloro-6-(4-fluorophenyl)-4-methyl-7-oxo-N-phe-
nyl-1,2,6,7-tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]-
naphthyridine-5-carboxamide (6c): isolated yield 412 mg (85%);
yellow powder; mp 193−195 °C; IR (KBr) ν 3262, 1668, 1645, 1597,
1
1521, 1440, 1219, 762, 717 cm−1; H NMR (DMSO-d6, 500 MHz) δ
2.21 (s, 3H), 4.20−4.51 (m, 4H), 5.35 (s, 1H), 7.00−7.91 (m, 12H),
9.79 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 14.9, 44.3, 98.6,
111.9, 114.5 (2JC−F = 20.8 Hz), 114.8, 119.5, 123.2, 125.3, 125.7,
127.6, 128.1, 129.0, 130.8, 134.6, 135.7, 138.3, 140.0, 147.0, 161.0
(1JC−F = 242.9 Hz), 166.6, 172.6; HRMS (ESI-TOF, [M + H]+) m/z
calcd for C28H22N3O2ClF 486.1385, found 486.1392.
ASSOCIATED CONTENT
■
S
* Supporting Information
General materials and methods, optimization of reaction
conditions for the synthesis of 6a from 5t, X-ray structure of
1
compound 5cc, H NMR study for the influence of o-chlorine,
Data for 9-chloro-6-(4-chlorophenyl)-4-methyl-7-oxo-N-
phenyl-1,2,6,7-tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]-
naphthyridine-5-carboxamide (6d): isolated yield 366 mg (73%);
gray powder; mp 205−207 °C; IR (KBr) ν 3256, 1668, 1616, 1596,
1H and 13C NMR spectra of all new compounds, and X-ray data
for compound 5cc in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
1521, 1441, 756, 693 cm−1; H NMR (CDCl3, 500 MHz) δ 2.45 (s,
3H), 4.04−4.22 (m, 4H), 5.29 (s, 1H), 6.90−8.18 (m, 12H), 8.34 (s,
1H); 13C NMR (DMSO-d6, 125 MHz) δ15.8, 45.4, 97.9, 112.1, 117.6,
120.2, 123.7, 125.0, 126.4, 127.2, 128.2, 129.0, 130.2, 131.6, 136.1,
139.7, 145.0, 148.2, 167.4, 172.4; HRMS (ESI-TOF, [M + H]+) m/z
calcd for C28H22N3O2Cl2 502.1089, found 502.1096.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: liming928@qust.edu.cn; wenlirong@qust.edu.cn.
Data for 6-(4-bromophenyl)-9-chloro-4-methyl-7-oxo-N-
phenyl-1,2,6,7-tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]-
naphthyridine-5-carboxamide (6e): isolated yield 392 mg (72%);
yellow powder; mp 218−220 °C; IR (KBr) ν 3270, 1667, 1616, 1596,
1521, 1441, 756, 692 cm−1; 1H NMR (DMSO-d6, 500 MHz) δ 2.21 (s,
3H), 4.19−4.50 (m, 4H), 5.34 (s, 1H), 7.00−7.89 (m, 12H), 9.84 (s,
1H); 13C NMR (DMSO-d6, 125 MHz) δ 15.8, 45.5, 97.9, 112.1, 117.6,
119.6, 120.3, 123.7, 125.0, 126.5, 127.2, 129.0, 130.6, 131.1, 131.6,
135.9, 136.1, 139.7, 145.4, 148.2, 167.4, 172.4; HRMS (ESI-TOF, [M
+ H]+) m/z calcd for C28H22N3O2BrCl 546.0584, found 546.0589.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (Grants 20872074 and
21072110) and the Natural Science Foundation of Shandong
Province (Grants ZR2010BM007 and ZR2012BM003).
K
dx.doi.org/10.1021/jo3013836 | J. Org. Chem. XXXX, XXX, XXX−XXX

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