Chemistry of heterocyclic ketene aminals: Construction of imidazo(pyrido)[1,2-a]pyridines and imidazo(pyrido)[3,2,1-ij][1,8]naphthyridines via DABCO-catalyzed tandem annulations

Article abstract of DOI:10.1021/jo102167g

2-(2-Chloroaroyl)methyleneimidazolidines with four reactive sites show fascinating structural features and could be used as a new strategy for the synthesis of novel heterocycles. This paper presents our new findings in the reaction of 2-(2-chloroaroyl)me

Full text of DOI:10.1021/jo102167g

ARTICLE
pubs.acs.org/joc
Chemistry of Heterocyclic Ketene Aminals: Construction of Imidazo
(pyrido)[1,2-a]pyridines and Imidazo(pyrido)[3,2,1-ij][1,8]-
naphthyridines via DABCO-Catalyzed Tandem Annulations
Ming Li,* Zhong-Min Zhou, Li-Rong Wen,* and Zhong-Xuan Qiu
State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of
Science and Technology, Qingdao 266042, P. R. China
S Supporting Information
b
ABSTRACT:
2-(2-Chloroaroyl)methyleneimidazolidines with four reactive sites show fascinating structural features and could be used as a new
strategy for the synthesis of novel heterocycles. This paper presents our new findings in the reaction of 2-(2-chloroaroyl)
methyleneimidazolidines with allenic esters affording functionalized imidazo(pyrido)[1,2-a]pyridines via DABCO-catalyzed
tandem annulations. Of particular significance is the incorporation of an o-halo group into the aryl ring of 2-benzoylmethylene-
imidazolidines to set up a convenient and general way for constructing unusual imidazo(pyrido)[3,2,1-ij][1,8]naphthyridines.
’ INTRODUCTION
Bicyclic pyridone motifs I (Figure 3) are of general interest
within medicinal chemistry with therapeutic properties, and a series
of substituted variants of I(n= 1, 2) have been reported as a basis for
analgesics and anti-inflammatory agents.8 In an early study, Huang2d
demonstrated a useful approach for bicyclic pyridones via azaꢀene
reaction of heterocyclic ketene aminals with ethyl propiolate.
Recently, Lin2i reported a novel reaction involving HKAs with β-
ketoester enol tosylates to synthesize bicyclic pyridones. These
approaches represent an important advance toward the objective of
a general method for the synthesis of motif I. Although much
progress has been achieved in synthesis of motif I, the preparation of
some specific substituted patterns remains difficult. It is of great
importance to explore novel and efficient synthetic methods in
order to meet the increasing scientific and practical demands.
So far, to the best of our knowledge, there have been no reports on
the synthetic application of HKAs with allenic esters to synthe-
size imidazo(pyrido)[1,2-a]pyridines. On the basis of the above
considerations and in the context of our efforts on developing
strategies toward heterocycles,9 herein we wish to present our new
findings in the reactions of novel HKAs 2 with allenic esters 3
affording functionalized imidazo(pyrido)[1,2-a]pyridines via DAB-
CO-catalyzed tandem annulations. Of particular significance is the
Polarized N,N-acetals1 1 have been proven to be important
synthons in the construction of heterocyclic systems. Reactions
of cyclic ketene aminals of the general formula 1 with a variety of
biselectrophilic reagents have so far been applied to make five-
and six-membered and fused heterocycles during the past years
(Figure 1).2
2-(2-Chloroaroyl)methyleneimidazolidines 2, as novel hetero-
cyclic ketene aminals (HKAs) with four reactive sites, show
fascinating structural features of a highly polarized pushꢀpull
interaction CdC double bond and a Cl atom as leaving group
(Figure 2). Since both R carbon and one secondary amino group
can take part in the reaction with electrophiles and another ortho
CꢀCl would be subject to SNAr reaction by attack of another
nitrogen atom, the precursors 2 display a different reactivity profile
in relation to that of 1 and could be applied to the construction of
novel heterocycles.
Meanwhile, allenes, which are endowed with features by the
presence of the cumulated diene structural unit, show unique
reactivity in organic synthesis. Over the past decade, chemical
transformations involving electron-deficient allenes have attracted
much research interest, with a number of new allene-based
reactions with high synthetic potentials having emerged.3ꢀ6 Some
of them have also been utilized in the syntheses of natural or
biological important compounds.7
Received: October 31, 2010
Published: March 30, 2011
r
2011 American Chemical Society
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Figure 1. Reactions of HKAs with biselectrophilics. [I] aryl azides;2a [II] 2-[3-oxoisobenzofuran-1(3H)-ylidene]malononitrile;2b [III] ethyl
2-(bromomethyl)benzoate;2c [IV] propiolic acid ester;2d [V] itaconic anhydride;2e [VI] Meldrum’s acid and aldehydes;2f [VII] bis-
(methylthio)methylene malononitrile;2g [VIII] BaylisꢀHillman acetates;2h [IX] polyhalo isophthalonitrile;2i [X] β-keto ester enol tosylates.2j
Table 1. Optimization of Reaction Conditions
entry catalyst (mmol %)
solvent
temp (°C) isolated yield (%)
Figure 2. Functionalized heterocyclic ketene aminals (HKAs).
1
Et3N (20)
Et3N (50)
Et3N (100)
CH3CN
CH3CN
CH3CN
CH3CN
THF
reflux
reflux
reflux
reflux
reflux
100
64
2
42
3
31
4
15
5
NaH (100)
21
6
NaH (100)
DMF
no reaction
7
DABCO (20)
DMAP (20)
Ph3P (20)
CH3CN
CH3CN
CH3CN
dioxane
C2H5OH
dioxane
reflux
reflux
reflux
reflux
reflux
reflux
77
70
48
88
82
83
8
9
Figure 3. Bicyclic pyridone motifs I.
10
11
12
DABCO (20)
DABCO (20)
DABCO (50)
successful incorporation of an o-halo group into the aryl ring of HKAs
1 to construct unusual imidazo(pyrido)[3,2,1-ij][1,8]naphthyridines.
dichlorophenyl)-2-(imidazolidin-2-ylidene)ethanone 2a with ethyl
hepta-2,3-dienoate 3a as a model. First, we examined the reaction in
the presence of 20 mmol % of Et3N, the compound 7-butyl-8-(2,4-
dichlorobenzoyl)-2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-one 4a
was obtained after stirring in refluxing CH3CN (Table 1, entry 1).
’ RESULTS AND DISCUSSION
Initially, we focused our efforts on searching for potential catalysts
and suitable reaction conditions by using the reaction of 1-(2,4-
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Table 2. DABCO-Catalyzed Formation of Imidazo(pyrido)[1,2-a]pyridine Derivatives
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Table 2. Continued
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Table 2. Continued
a Yield of isolated product.
Next, other attempts were also made. For example, we tried adding
50 mmol % Et3N and adding 100 mmol % Et3N and also tried
without Et3N (Table 1, entries 2ꢀ4). However, the yields of
product 4a were not satisfactory. Then, we used other various
bases, including 100 mmol % NaH, 20 mmol % 1,4-diazabicyclo-
(2.2.2)octane (DABCO), 20 mmol % DMAP, and 20 mmol %
Lewis base Ph3P, in a variety of solvents (Table 1, entries 5ꢀ11). To
our delight, a break-through result was obtained when 20 mmol %
DABCO was added to a solution of 3a and 2a in dioxane (Table 1,
entry 10), in which 4a was formed in good yield of 88%. Then we
tried increasing the amount of DABCO to 50 mmol % but could not
get a better yield of the desired product 4a (Table 1, entry 12). So
the optimum reaction conditions were dioxane as the solvent and
20 mmol % DABCO as the base (Table 1, entry 10). Compared to
other bases, DABCO has been regarded as an unhindered and
nucleophilic base and considered one of the best amine catalysts due
to its unique properties.10ꢀ13
Next this methodology was also extended for the synthesis of
pyrido[1,2-a]pyridines following a similar sequence by subjecting
1-(2,4-dichlorophenyl)-2-(tetrahydro pyrimidin-2(1H)-ylidene)-
ethanone 20a to Michael addition/imineꢀenamine tautomeriza-
tion with ethyl hepta-2,3-dienoate 3a under identical conditions
to give 8-butyl-9-(2,4-dichlorobenzoyl)-1,2,3,4-tetrahydropyrido-
[1,2-a]pyrimidin-6-one 5a.
(Table 2, entries 1ꢀ4 and 7ꢀ10); (2) the size of heterocycles of
heterocyclic ketene aminals; generally, five-membered HKAs often
give higher yields than six-membered ones, for example, the reactions
of 2a or 2b with 3d gave 65% or 75%, respectively, whereas 20a or 20b
produced yields of only 45% or 33% (Table 2, entries 4 and 18, entries
6 and 20); (3) the substituents on the aryl ring of HKA; the effects of
various substituents on the aryl rings of HKAs used in our experi-
ments on the reaction yields did not show obvious regularities.
The structural determination of all products was achieved by
1
their H NMR, 13C NMR, IR ,and HRMS spectroscopic data,
which are in agreement with the proposed structures, and
unequivocally confirmed by X-ray diffraction analysis of product
4a (see Supporting Information).
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 applications.11 Therefore,
the synthesis of imidazo(pyrido)[3,2,1-ij][1,8]naphthyridines
may be of great significance.
Our studies highlighted the concept of a substrate-design
approach to the development of novel tandem reactions. As a
result of incorporating an o-halo group into the aryl ring in the
Scheme 1. Synthesis of Imidazo(pyrido)[3,2,1-ij]-
With the optimized conditions in hand, we explored the scope of
this reaction, and these results are shown in Table 2. The reactions
of 2/20 with 3 proceeded smoothly to afford imidazo(pyrido)-
[1,2-a]pyridine derivatives 4/5 in moderate to good yields. As can
be seen from Table 2, there may be three factors influencing the yields
of 4/5: (1) the size of the substituents on allenic esters; the allenic
esters with relatively smaller substituents often give higher yields, for
example, 3a or 3c gave higher yields than 3b or 3d, respectively
[1,8]naphthyridines 6/7 from 4/5
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Scheme 2. Plausible Reaction Mechanism (e.g., Products 6)
HKA motif of 4/5, we reasoned the subsequent intramolecular
SNAr reaction could occur ortho-selectively to form new fused
imidazo(pyrido)[3,2,1-ij][1,8]naphthyridines 6/7. So we directly
explored the reactions of all of 4/5 in the presence of K2CO3
(1.0 equiv) in DMF at100 °C forabout6 h monitored byTLC. To
our surprise, except 4b and 4c, all other 4/5 gave the correspond-
ing imidazo(pyrido)[3,2,1-ij][1,8]naphthyridines 6/7 in almost
quantitative yields of 95ꢀ99% (Scheme 1). For that, we carefully
examined the intramolecular SNAr reactions of 4b and 4c in the
presence of various other basic catalysts such as Na2CO3, NaOH,
and NaH. However, we found that in all cases they could not react
at all without any reasons for explanation.
allenic esters has been demonstrated, which opens the efficient
and flexible way to synthesis of imidazo(pyrido)[1,2-a]pyridine and
imidazo(pyrido)[3,2,1-ij][1,8]naphthyridine derivatives. On the
basis of the experimental results in this domino reaction, nine
reactive sites are involved; one CꢀC bond, two CꢀN bonds, and
two new rings are constructed with all reactants efficiently utilized in
the chemical transformation. A possible mechanism involving the
ring-closure cascade reactions, including formation of zwitterion,
Michael addition, intramolecular imineꢀenamine tautomerization,
followed by cyclocondensation and intramolecular SNAr, is repre-
sented. Further investigations to expand the scope of the diversity-
oriented synthesis of 2-(2-chloroaroyl)methyleneimidazolidines as
versatile building blocks are in progress and will be reported.
The structures of all products 6/7 were characterized by IR,
1H, 13C NMR, HRMS spectroscopy and further confirmed by
X-ray diffraction analysis of product 6g (see the Supporting
Information).
’ EXPERIMENTAL SECTION
It is worthwhile to point out that the synthesis of imidazo-
(pyrido)[3,2,1-ij][1,8] naphthyridines has been scarcely re-
ported with only two similar examples in the literatures.1,14
Obviously, our novel strategy provides a more general and facile
route to synthesize this type of compounds.
On the basis of the above results, a plausible mechanism for
this reaction is proposed as shown in Scheme 2. Take products 6, for
example. Initially DABCO as a nucleophilic trigger reacts with
allenic esters 3 to generate the zwitterionic intermediates A,15 which
abstracts a proton from 2 to produce C. Subsequent Michael
addition of B to C gives another zwitterions D. The elimination
of DABCO from D affords E. Then, the intermediates E undergo a
rapid imineꢀenamine tautomerization to give F, and intramolecular
cyclization of F leads to the formation of dihydroimidazo[1,2-a]
pyridine(1H)-ones 4. Finally, an intramolecular SNAr of the o-
chloro of aryl group by attack of NH group generates imidazo[3,2,1-
ij][1,8]naphthyridine derivatives 6 with elimination of HCl.
General Procedure for the Preparation of Products 4 or 5
(e.g., 4a). DABCO (0.092 g, 0.4 mmol) was added to a solution of ethyl
hepta-2,3-dienoate 3a (0.370 g, 2.4 mmol) and 1-(2,4-dichloro-phenyl)-
2-(imidazolidin-2-ylidene)ethanone 2a (0.514 g, 2.0 mmol) in 1,4-
dioxene (30 mL). Then the mixture was heated at reflux for about 20 h.
After the completion of the reaction as indicated by TLC (petroleum
etherꢀEtOAc, 1:2, v/v) and cooling to room temperature, the solvent
was removed in vacuum, and the residue was purified by the column
chromatography to afford pure compound 4a.
General Procedure for Synthesis of Products 6 or 7 (e.g., 6a).
A mixture of corresponding 4a (0.365 g, 1.0 mmol) and K2CO3 (0.138 g,
1.0 mmol) was heated to 100 °C in DMF (15 mL). After the completion
of the reaction as indicated by TLC (petroleum etherꢀEtOAc, 1:4, v/v)
at about 6 h, the mixture was cooled to room temperature. An amount
of iceꢀwater was added to precipitate the product, which was then
filtered and washed with small amount of ethanol to give the pure
product 6a.
7-Butyl-8-(2,4-dichlorobenzoyl)-2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-
one (4a). Light yellow solid; mp 172ꢀ174 °C; IR (KBr, cmꢀ1) 1663,
1602, 1558, 825; 1H NMR (CDCl3) δ 9.01 (s,1H), 7.21ꢀ7.44
(m, 3H), 5.69 (s, 1H), 4.25 (t, J = 9.0 Hz, 2H), 3.98 (t, J = 9.0 Hz,
2H), 1.95 (s, w, 2H), 1.27 (s, w, 2H), 0.93ꢀ1.00 (m, 2H), 0.72 (t, J = 7.0
Hz, 3H); 13C NMR (CDCl3) δ 189.8, 160.8, 158.2, 156.2, 140.2, 135.8,
131.6, 129.9, 129.2, 127.2, 108.6, 98.4, 43.2, 42.7, 34.4, 32.1, 22.4, 13.5;
’ CONCLUSION
In summary, this study highlighted the concept of a substrate-
design approach to the development of novel tandem reactions by
incorporating an o-halo group into the aryl ring of heterocyclic
ketene aminals. A novel DABCO-catalyzed tandem annulation
between 2-(2-chloroaroyl)methyleneimidazo(pyrido)lidines and
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HRMS (ESI-TOF, [M þ H]þ) calcd for C18H19N2O2Cl2, 365.0824,
found 365.0806.
6-Benzyl-8-(2,5-dichlorobenzoyl)-7-pentyl-2,3-dihydroimidazo[1,2-a]pyr-
idin-5(1H)-one (4f). Yellow solid; mp 139ꢀ141 °C; IR (KBr, cmꢀ1
)
1
1646, 1594, 1558, 814, 784, 696; H NMR (CDCl3) δ 8.86 (s, 1H),
7.12ꢀ7.31 (m, 8H), 4.28 (t, J = 8.0 Hz, 2H), 3.95 (t, J = 8.0 Hz, 2H), 3.89
10-Chloro-benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyridine-6-butyl-
4,7-dione (6a). White solid; mp 220ꢀ222 °C; IR (KBr, cmꢀ1) 1671,
1633, 1605, 1575, 1534, 949, 883, 833, 773; 1H NMR (CDCl3)
δ 8.30 (d, J = 8.5 Hz, 1H), 7.11ꢀ7.31 (m, 2H), 6.05 (s, 1H),
4.48ꢀ4.55 (m, 4H), 3.11 (t, J = 7.5 Hz, 2H), 1.57ꢀ1.63 (m, 2H),
1.42ꢀ1.50 (m, 2H), 0.96 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3) δ
174.0, 160.1, 157.6, 149.0, 139.2, 136.9, 129.4, 124.0, 123.3, 113.6, 113.4,
100.8, 44.6, 43.1, 34.2, 31.7, 22.5, 13.9; HRMS (ESI-TOF, [M þ H]þ)
calcd for C18H18N2O2Cl, 329.1057, found 329.1056.
(s, 2H), 2.12 (s, w, 2H), 1.01ꢀ1.09 (s, w, 4H), 0.72ꢀ0.75 (m, 5H); 13
C
NMR (CDCl3) δ 189.4, 161.1, 156.8, 152.2, 142.9, 140.7, 132.9, 131.0,
130.2, 128.9, 128.2, 128.2, 127.9, 125.7, 117.6, 98.1, 43.8, 42.4, 31.9,
31.4, 30.8, 30.2, 22.3, 13.8; HRMS (ESI-TOF, [M þ H]þ) calcd for
C26H27N2O2Cl2, 469.1450, found 469.1434.
9-Chloro-benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyridine-5-benzyl-
6-pentyl-4,7-dione (6f). White solid; mp 177ꢀ179 °C; IR (KBr, cmꢀ1
)
1652, 1630, 1594, 1569, 1542, 1509, 806, 748, 696; 1H NMR (CDCl3) δ
8.37 (d, J = 14.0 Hz, 1H), 7.04ꢀ7.56 (m, 7H), 4.47ꢀ4.56 (m, 4H), 4.02
(s, 2H), 3.27 (s, w, 2H), 1.44 (s, w, 4H), 1.31ꢀ1.34 (m, 2H), 0.88 (t, J =
7.0 Hz, 3H); 13C NMR (CDCl3) δ 173.8, 161.0, 153.9, 147.9, 140.8,
134.7, 133.0, 129.6, 128.6, 128.5, 127.9, 126.4, 126.3, 123.8, 115.2, 101.0,
44.8, 44.0, 32.7, 31.5, 31.0, 30.0, 22.9, 14.4; HRMS (ESI-TOF, [M þ
H]þ) calcd for C26H26N2O2Cl, 433.1683, found 433.1680.
7-Benzyl-8-(2,4-dichlorobenzoyl)-2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-
one (4b). Light yellow solid; mp 185ꢀ186 °C; IR (KBr, cmꢀ1) 1669,
1
1594, 1567, 978, 828, 782, 731; H NMR (CDCl3) δ 9.14 (s, 1H),
6.81ꢀ7.45 (m, 8H), 5.49 (s, 1H), 4.26 (t, J = 9.0 Hz, 2H), 3.99 (t, J = 9.0
Hz, 2H), 3.37 (s, 2H); 13C NMR (CDCl3) δ 192.1, 163.0, 160.8, 155.9,
142.7, 140.1, 138.3, 133.8, 132.2, 131.6, 131.2, 130.9, 129.7, 129.1, 113.3,
101.2, 45.6, 45.2, 42.9; HRMS (ESI-TOF, [M þ H]þ) calcd for
C21H17N2O2Cl2, 365.0667, found 365. 0658.
7-Butyl-8-(2-chlorobenzoyl)-2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-
one (4g). Light yellow solid; mp 138ꢀ140 °C; IR (KBr, cmꢀ1) 1663,
1602, 1561, 1550, 762; 1H NMR (CDCl3) δ 9.07 (s, 1H), 7.25ꢀ7.41
(m, 4H), 5.67 (s, 1H), 4.23 (t, J = 8.5 Hz, 2H), 3.96 (t, J = 8.5 Hz, 2H),
1.91 (s, w, 2H), 1.25 (s, w, 2H), 0.86ꢀ0.93 (m, 2H), 0.68 (t, J = 7.0 Hz,
3H); 13C NMR (CDCl3) δ 191.0, 160.8, 158.2, 156.6, 141.8, 130.5,
130.0, 128.2, 126.8, 108.3, 98.5, 43.1, 42.6, 34.3, 32.1, 22.4, 13.5; HRMS
(ESI-TOF, [M þ H]þ) calcd for C18H20N2O2Cl, 331.1213, found
331.1220.
6-Benzyl-8-(2,4-dichlorobenzoyl)-7-methyl-2,3-dihydroimidazo[1,2-a]
pyridin-(1H)-one (4c). White solid; mp 173ꢀ175 °C; IR (KBr, cmꢀ1
)
1714, 1649, 1584, 1560, 990, 826, 781, 699; 1H NMR (CDCl3) δ 8.90 (s,
1H), 7.12ꢀ7.41 (m, 8H), 4.28 (t, J = 8.5 Hz, 2H), 3.95 (t, J = 8.5 Hz, 2H),
3.88 (s, 2H), 1.68 (s, 3H); 13C NMR (CDCl3) δ 190.0, 160.8, 156.4, 147.3,
141.0, 140.3, 135.6, 131.3, 129.9, 129.0, 128.2, 128.0, 127.4, 125.7, 118.5,
99.6, 43.7, 42.4, 31.6, 19.4; HRMS (ESI-TOF, [M þ H]þ) calcd for
C22H19N2O2Cl2, 413.0824, found 413.0834.
Benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyridine-6-butyl-4,
7-dione (6g). White solid; mp 224ꢀ226 °C; IR (KBr, cmꢀ1) 1668,
6-Benzyl-8-(2,4-dichlorobenzoyl)-7-pentyl-2,3-dihydroimidazo[1,2-a]
pyridin-5(1H)-one (4d). White solid; mp 145ꢀ147 °C; IR (KBr, cmꢀ1
)
1
1650, 1597, 1583, 1561, 826, 782, 728, 698; 1H NMR (CDCl3) δ 8.79 (s,
1H), 7.12ꢀ7.42 (m, 8H), 4.26 (t, J = 9.0 Hz, 2H), 3.90 (t, J = 9.0 Hz, 2H),
3.88 (s, 2H), 2.12 (s, w, 2H), 1.00ꢀ1.07 (m, 4H), 0.72ꢀ0.75 (m, 5H); 13C
NMR (CDCl3) δ 190.1, 161.2, 156.7, 152.3, 140.9, 140.1, 135.8, 131.7,
129.9, 129.4, 128.2, 128.0, 127.2, 125.7, 117.7, 98.3, 43.8, 42.4, 31.9, 31.5,
30.9, 30.1, 22.3, 13.9; HRMS (ESI-TOF, [M þ H]þ) calcd for
C26H27N2O2Cl2, 469.1450, found 469.1439.
1622, 1575, 1545, 1509, 754; H NMR (CDCl3) δ 8.36 (dd, J1 =
7.0 Hz, J2 = 1.0 Hz, 1H), 7.07ꢀ7.64 (m, 3H), 6.00 (s, 1H), 4.49 (s, 4H),
3.11 (t, J = 7.5 Hz, 2H), 1.57ꢀ1.63 (m, 2H), 1.42ꢀ1.49 (m, 2H), 0.95 (t,
J = 7.5 Hz, 3H); 13C NMR (CDCl3) δ 174.8, 160.3, 157.8, 148.8, 136.1,
132.8, 127.6, 124.8, 123.4, 113.5, 113.2, 100.7, 44.5, 43.1, 34.3, 31.8, 22.5,
14.0; HRMS (ESI-TOF, [M þ H]þ) calcd for C18H19N2O2, 295.1447,
found 295.1454.
10-Chloro-benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyridine-5-benzyl-
7-Benzyl-8-(2-chlorobenzoyl)-2,3-dihydroimidazo[1,2-a]pyridin-5-
(1H)-one (4h). Yellow solid; mp 181ꢀ183 °C; IR (KBr, cmꢀ1) 1670,
1592, 1563, 979, 767, 744; 1H NMR (CDCl3) δ 9.16 (s, 1H), 6.81ꢀ7.38
(m, 9H), 5.45 (s, 1H), 4.25 (t, J = 9.0 Hz, 2H), 4.00 (t, J = 9.0 Hz, 2H),
3.32 (s, 2H); 13C NMR (CDCl3) δ 190.8, 160.6, 158.2, 154.2, 141.8,
137.8, 130.5, 130.3, 129.9, 129.0, 128.4, 128.1, 126.9, 126.5, 110.4, 98.9,
6-pentyl-4,7-dione (6d). White solid; mp 264ꢀ266 °C; IR (KBr, cmꢀ1
)
1651, 1634, 1607, 1568, 1540, 840, 788, 741, 699; 1H NMR (CDCl3) δ
8.32 (d, J = 8.5 Hz, 1H), 7.09ꢀ7.28 (m, 7H), 4.54 (t, J = 8.5 Hz, 2H),
4.43 (t, J = 8.5 Hz, 2H), 4.01 (s, 2H), 3.26 (s, w, 2H), 1.42ꢀ1.45 (m,
4H), 1.28ꢀ1.35 (m, 2H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3) δ
174.1, 160.6, 153.7, 147.7, 140.4, 138.9, 136.8, 129.8, 128.3, 128.2, 125.9,
123.8, 123.5, 113.2, 100.8, 44.3, 43.6, 32.4, 31.2, 30.7, 29.7, 22.6, 14.1;
HRMS (ESI-TOF, [M þ H]þ) calcd for C26H26N2O2Cl, 433.1683,
found 433.1693.
43.2, 42.7, 40.2; HRMS (ESI-TOF, [M
C21H18N2O2Cl, 365.1057, found 365.1068.
þ
H]þ) calcd for
Benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyridine-6-benzyl-47-dione
(6h). White solid; mp 289ꢀ291 °C; IR (KBr, cmꢀ1) 1668, 1627, 1608,
1577, 1549, 760, 720; 1H NMR (CDCl3) δ 8.41 (d, J =
7.5 Hz, 1H), 7.09ꢀ7.68 (m, 8H), 5.93 (s, 1H), 4.61 (s, 2H), 4.51
(s, 4H); 13C NMR (CDCl3) δ 175.1, 160.2, 156.2, 148.8, 138.6, 136.2,
133.0, 129.5, 128.5, 128.0, 126.5, 124.9, 123.6, 114.4, 113.5, 100.6, 44.6,
43.2, 39.6; HRMS (ESI-TOF, [M þ H]þ) calcd for C21H17N2O2,
329.1290, found 329.1278.
7-Butyl-8-(2,5-dichlorobenzoyl)-2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-
one (4e). Light yellow solid; mp 139ꢀ141 °C; IR (KBr, cmꢀ1) 1668,
1602, 1545, 979, 809; 1H NMR (CDCl3) δ 9.08 (s, 1H), 7.33ꢀ7.43 (m,
3H), 5.75 (s, 1H), 4.26 (t, J = 8.5 Hz, 2H), 4.00 (t, J = 8.5 Hz, 2H), 1.95
(s, w, 2H), 1.29 (s, w, 2H), 0.95 (s, w, 2H), 0.73 (t, J = 4.5 Hz, 3H); 13C
NMR (CDCl3) δ 188.9, 160.6, 158.3, 156.1, 143.0, 132.9, 131.1, 130.2,
128.8, 128.0, 108.5, 98.1, 43.1, 42.6, 34.2, 32.1, 22.4, 13.5; HRMS (ESI-
TOF, [M þ H]þ) calcd for C18H19N2O2Cl2, 365.0824, found
365.0833.
9-Chloro-benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyridine-6-butyl-
4,7-dione (6e). White solid; mp 237ꢀ239 °C; IR (KBr, cmꢀ1) 1663,
1635, 1578, 1542, 1509, 836; 1H NMR (CDCl3) δ 8.32 (s, 1H), 7.58 (d,
J = 7.5 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.07 (s, 1H), 4.55 (s, 4H), 3.11
(t, J = 7.5 Hz, 2H), 1.57ꢀ1.63 (m, 2H), 1.46ꢀ1.49 (m, 2H), 0.97 (t, J =
7.0 Hz, 3H); 13C NMR (CDCl3) δ 173.5, 160.2, 157.8, 148.9, 134.6,
132.9, 129.6, 127.5, 125.9, 115.1, 113.6, 100.8, 44.8, 43.3, 34.3, 31.8, 22.5,
13.9; HRMS (ESI-TOF, [M þ H]þ) calcd for C18H18N2O2Cl,
329.1057, found 329.1042.
6-Benzyl-8-(2-chlorobenzoyl)-7-methyl-2,3-dihydromidazo[1,2-a]pyri-
)
din-5(1H)-one (4i). Yellow solid; mp 190ꢀ192 °C; IR (KBr, cmꢀ1
1
1647, 1597, 1567, 1544, 777, 749, 695; H NMR (CDCl3) δ 8.94 (s,
1H), 7.11ꢀ7.39 (m, 9H), 4.26 (t, J = 9.0 Hz, 2H), 3.92 (t, J = 9.0 Hz,
2H), 3.87 (s, 2H), 1.66 (s, 3H); 13C NMR (CDCl3) δ 193.8, 163.4,
158.9, 150.3, 145.1, 142.9, 132.8, 132.5, 130.7, 130.5, 129.5, 128.2, 120.7,
102.3, 46.2, 44.9, 34.2, 21.7; HRMS (ESI-TOF, [M þ H]þ) calcd for
C22H20N2O2Cl, 379.1213, found 379.1214.
Benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyridine-5-benzyl-6-
methyl-4,7-dione (6i). White solid; mp >300 °C; IR (KBr, cmꢀ1) 1652,
1629, 1609, 1574, 1551, 884, 764, 704; 1H NMR (CDCl3) δ 8.39 (d, J =
8.0 Hz, 1H), 7.10ꢀ7.62 (m, 8H), 4.48ꢀ4.58 (m, 4H), 4.03 (s, 2H), 1.61
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(s, 3H); 13C NMR (CDCl3) δ 178.1, 162.9, 151.8, 149.7, 142.5, 138.6,
135.2, 130.8, 130.5, 128.4, 127.7, 126.2, 125.8, 115.7, 103.7, 46.8, 46.1,
33.9, 20.6; HRMS (ESI-TOF, [M þ H]þ) calcd for C22H19N2O2,
343.1447, found 343.1453.
6-Benzyl-8-(2-chlorobenzoyl)-7-pentyl-2,3-dihydroimidazo[1,2-a]pyri-
din-5(1H)-one (4j). White solid; mp 120ꢀ122 °C; IR (KBr, cmꢀ1) 1645,
1590, 1557, 761, 699; 1H NMR (CDCl3) δ 8.83 (s, 1H), 7.12ꢀ7.40 (m,
9H), 4.29 (t, J = 9.0 Hz, 2H), 3.95 (t, J = 9.0 Hz, 2H), 3.88 (s, 2H), 2.11 (s,
w, 2H), 0.98ꢀ1.05 (m, 4H), 0.70ꢀ0.73 (m, 5H); 13C NMR (CDCl3) δ
191.5, 161.2, 156.7, 152.8, 141.6, 140.9, 130.7, 130.4, 130.0, 128.4, 128.2,
128.0, 126.8, 125.7, 117.4, 98.5, 43.8, 42.4, 31.9, 31.5, 30.8, 30.1, 22.2, 13.9;
HRMS (ESI-TOF, [M þ H]þ) calcd for C26H28N2O2Cl, 435.1839, found
435.1837.
129.6, 128.3, 128.0, 125.8, 121.1, 119.5, 118.4, 116.7, 99.9, 43.9, 42.5,
31.8, 19.4; HRMS (ESI-TOF, [M þ H]þ) calcd for C28H23N3O2Cl2,
505.1086, found 505.1096.
10-(4-Chlorophenoxy)-benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphth-
yridine-5- benzyl-6-methyl-4,7-dione (6m). White solid; mp 270ꢀ272 °C;
IR (KBr, cmꢀ1) 1652, 1636, 1613, 1572, 1548, 1478, 824, 781, 739, 699; 1H
NMR (CDCl3) δ 8.31 (d, J = 9.0 Hz, 1H), 6.58ꢀ7.40 (m, 11H), 4.53 (t, J =
8.5 Hz, 2H), 4.36 (t, J = 8.5 Hz, 2H), 4.02 (s, 2H), 2.83 (s, 3H); 13C NMR
(CDCl3) δ175.1, 161.4, 160.4, 153.9, 149.3, 147.4, 140.0 137.7, 130.4, 130.3,
128.4, 128.3, 126.0, 123.8, 121.6, 120.6, 113.4, 101.2, 44.4, 43.6, 31.5, 18.2;
HRMS (ESI-TOF, [M þ H]þ) calcd for C28H22N2O2Cl, 469.1319, found
469.1325.
7-Butyl-8-(2-fluoro-4-methoxybenzoyl)-2,3-dihydroimidazo[1,2-a]
pyridin-5(1H)-one (4n). Light yellow solid; mp 122ꢀ124 °C; IR
(KBr, cmꢀ1) 1664, 1621, 1597, 1575, 1554, 849, 802; 1H NMR
(CDCl3) δ 8.40 (s, 1H), 7.34 (t, J = 8.5 Hz, 1H), 6.74 (dd, J1 = 8.5
Hz, J2 = 2.5 Hz, 1H), 6.62 (dd, J1 = 6.5 Hz, J2 = 2.0 Hz, 1H), 5.71 (s, 1H),
4.24 (t, J = 9.0 Hz, 2H), 3.93 (t, J = 9.0 Hz, 2H), 2.12 (t, J = 7.5 Hz, 2H),
1.22ꢀ1.28 (m, 2H), 0.94ꢀ1.02 (m, 2H), 0.70 (t, J = 7.5 Hz, 3H); 13C
NMR (CDCl3) δ 189.1, 163.0, 161.4, 160.9, 159.4, 157.3, 156.9, 130.6,
123.0, 110.2, 108.3, 101.9, 101.7, 99.2, 55.8, 43.4, 42.6, 34.4, 32.4, 22.3,
13.6; HRMS (ESI-TOF, [M þ H]þ) calcd for C19H22N2O3F, 345.1614,
found 345.1625.
Benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyridine-5-benzyl-6-
pentyl-4,7-dione (6j). White solid; mp 237ꢀ239 °C; IR (KBr, cmꢀ1
)
1648, 1609, 1572, 1549, 758, 701; 1H NMR (CDCl3) δ 8.39 (d, J = 8.0
Hz, 1H), 7.05ꢀ7.55 (m, 8H), 4.42ꢀ4.53 (m, 4H), 4.02 (s, 2H), 3.29 (s,
w, 2H), 1.46 (s, w, 4H), 1.29ꢀ1.37 (m, 2H), 0.89 (t, J = 7.0 Hz, 3H); 13
C
NMR (CDCl3) δ 174.9, 160.8, 153.9, 147.5, 140.6, 136.0, 132.6, 128.3,
128.2, 128.0, 125.9, 125.1, 123.2, 123.0, 113.2, 100.6, 44.2, 43.6, 32.4,
31.1, 30.7, 29.7, 22.6, 14.1; HRMS (ESI-TOF, [M þ H]þ) calcd for
C26H27N2O2, 399.2073, found 399.2066.
7-Butyl-8-(2,4-dichloro-5-fluorobenzoyl)-2,3-dihydroimidazo[1,2-
a]pyridin-5(1H)-one (4k). Light yellow solid; mp 169ꢀ171 °C; IR
(KBr, cmꢀ1) 1663, 1594, 1561, 883; 1H NMR (CDCl3) δ 9.02 (s, 1H),
7.48 (d, J = 7.5 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 5.70 (s, 1H), 4.25 (t, J =
9.0 Hz, 2H), 3.99 (t, J = 9.0 Hz, 2H), 1.97 (s, w, 2H), 1.29 (s, w, 2H),
0.95ꢀ1.03 (m, 2H), 0.73 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3) δ
188.0, 160.6, 158.3, 155.8, 141.6, 131.6, 126.1, 123.0, 116.2, 116.1, 108.7,
98.0, 43.1, 42.7, 34.2, 32.0, 22.4, 13.5; HRMS (ESI-TOF, [M þ H]þ)
calcd for C18H18N2O2Cl2F, 383.0729, found 383.0712.
10-Methoxy-benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyridine-
6-butyl-4,7-dione (6n). White solid; mp 234ꢀ236 °C; IR (KBr, cmꢀ1
)
1672, 1615, 1577, 1548, 1489, 866, 813, 779; 1H NMR (CDCl3) δ 8.24
(d, J = 8.5 Hz, 1H), 6.85 (dd, J1 = 8.5 Hz, J2 = 2.0 Hz, 1H), 6.38 (d, J = 2.0
Hz, 1H), 5.97 (s, 1H), 4.39ꢀ4.49 (m, 4H), 3.10 (t, J = 7.5 Hz, 2H),
1.56ꢀ1.62 (m, 2H), 1.42ꢀ1.49 (m, 2H), 0.95 (t, J = 7.0 Hz, 3H); 13C
NMR (CDCl3) δ 174.5, 163.4, 160.2, 157.9, 148.9, 137.9, 129.6 118.7,
113.0, 110.5, 100.3, 97.6, 55.7, 44.5, 43.1, 34.3, 31.8, 22.6, 14.0; HRMS
(ESI-TOF, [M þ H]þ) calcd for C19H21N2O3, 325.1552, found
325.1562.
9-Fluoro-10-chloro-benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyrid-
ine-6-butyl-4,7-dione (6k). White solid; mp 242ꢀ244 °C; IR (KBr, cmꢀ1
)
1667, 1641, 1611, 1599, 1575, 1548, 1509, 846; 1HNMR(CDCl3) δ8.10 (d,
J = 7.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 6.06 (s, 1H), 4.48ꢀ4.56 (m, 4H),
3.09 (t, J= 7.5 Hz, 2H), 1.55ꢀ1.61 (m, 2H), 1.41ꢀ1.49 (m, 2H), 0.95 (t, J =
6.5 Hz, 3H) ; 13C NMR (CDCl3) δ 173.2, 160.1, 157.6, 155.6, 153.6, 149.1,
132.8, 127.1, 127.0, 124.8, 115.6, 114.8, 114.6, 113.8, 100.4, 44.9, 43.1, 34.2,
31.8, 22.5, 13.9; HRMS (ESI-TOF, [M þ H]þ) calcd for C18H17N2O2ClF,
347.0963, found 347.0967.
8-Butyl-9-(2,4-dichlorobenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]
pyrimidin-6-one (5a). Light yellow solid; mp 148ꢀ150 °C; IR
1
(KBr, cmꢀ1) 1660, 1564, 861, 839, 811, 789; H NMR (CDCl3) δ
11.42 (s, 1H), 7.21ꢀ7.45 (m, 3H), 5.78 (s, 1H), 4.09 (t, J = 6.0 Hz, 2H),
3.54 (t, J = 6.0 Hz, 2H), 2.09ꢀ2.14 (m, 2H), 1.89 (t, J = 7.0 Hz, 2H), 1.28
(s, w, 2H), 0.95ꢀ1.03 (m, 2H), 0.73 (t, J = 7.5 Hz, 3H); 13C NMR
(CDCl3) δ 190.2, 161.6, 156.4, 155.4, 141.0, 136.1, 132.3, 130.4, 130.0,
127.4, 107.0, 99.4, 39.7, 39.1, 35.8, 32.4, 22.7, 19.4, 13.8; HRMS (ESI-
TOF, [M þ H]þ) calcd for C19H21N2O2Cl2, 379.0980, found 379.0966.
11-Chloro-benzo-1,2,3-trihydropyrido[3,2,1-ij][1,8]naphthyridine-7-
7-Butyl-8-(2-chloro-4-(4-chlorophenoxy)benzoyl)-2,3-dihydroimidazo-
[1,2-a]pyridin-5(1H)-one (4l). Light yellow solid; mp 156ꢀ158 °C; IR
(KBr, cmꢀ1) 1663, 1588, 1565, 1484, 830; 1H NMR (CDCl3) δ 8.94 (s,
1H), 6.89ꢀ7.36 (m, 7H), 5.69 (s, 1H), 4.24 (t, J = 8.5 Hz, 2H), 3.97 (t, J =
8.5 Hz, 2H), 1.99 (s, w, 2H), 1.28 (s, w, 2H), 0.96ꢀ1.03 (m, 2H), 0.73 (t, J=
7.0 Hz, 3H); 13C NMR (CDCl3) δ 190.4, 158.7, 158.2, 156.5, 154.4, 136.8,
132.2, 130.2, 129.8, 121.0, 119.5, 116.5, 108.5, 98.6, 43.3, 42.7, 34.5, 32.1,
22.6, 13.6; HRMS (ESI-TOF, [M þ H]þ) calcd for C24H23N2O3Cl2,
457.1086, found 457.1096.
butyl-5,8-dione (7a). White solid; mp 239ꢀ241 °C; IR (KBr, cmꢀ1
)
1660, 1622, 1589, 1569, 1506, 943, 924, 875, 844, 776; 1H NMR
(CDCl3) δ 8.34 (d, J = 8.5 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J = 8.5 Hz,
1H), 6.20 (s, 1H), 4.30 (s, w, 2H), 4.21 (s, w, 2H), 3.17 (t, J = 7.5 Hz,
2H), 2.36 (s, w, 2H), 1.56ꢀ1.62 (m, 2H), 1.43ꢀ1.50 (m, 2H), 0.95 (t, J =
7.0 Hz, 3H); 13C NMR (CDCl3) δ 174.6, 160.8, 156.9, 147.1, 140.0,
139.1, 128.8, 124.3, 123.2, 114.4, 113.2, 104.3, 46.3, 38.8, 35.8, 32.1, 22.7,
19.6, 14.0; HRMS (ESI-TOF, [M þ H]þ) calcd for C19H20N2O2Cl,
343.1213, found 343.1223.
10-(4-Chlorophenoxy)-benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphth-
yridine-6-butyl-4,7-dione (6l). White solid; mp 227ꢀ229 °C; IR
1
(KBr, cmꢀ1) 1667, 1633, 1611, 1576, 1546, 1477, 839, 787; H NMR
8-Benzyl-9-(2,4-dichlorobenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]
(CDCl3) δ 8.32 (d, J = 9.0 Hz, 1H), 6.60ꢀ7.40 (m, 6H), 6.03 (s, 1H),
4.39ꢀ4.50 (m, 4H), 3.13(t, J = 7.5 Hz, 2H), 1.58ꢀ1.64 (m, 2H), 1.42ꢀ1.50
(m, 2H), 0.95 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3) δ 174.4, 161.6, 160.3,
158.0, 153.8, 149.1, 137.9, 130.3, 121.6, 120.5, 113.5, 113.4, 101.4, 100.6,
44.7, 43.1, 34.4, 31.9, 22.6, 14.1; HRMS (ESI-TOF, [M þ H]þ) calcd for
C24H22N2O3Cl, 421.1319, found 421.1316.
6-Benzyl-8-(2-chloro-4-(4-chlorophenoxy)benzoyl)-7-methyl-2,3-
dihydroimidazo [1,2-a]pyridin-5(1H)-one (4m). Light yellow solid; mp
157ꢀ159 °C; IR (KBr, cmꢀ1) 1644, 1601, 1584, 1484, 689; 1H NMR
(CDCl3) δ 8.81 (s, 1H), 6.87ꢀ7.35 (m, 12H), 4.29 (t, J = 9.0 Hz, 2H),
3.96 (t, J = 9.5 Hz, 2H), 3.89 (s, 2H), 1.72 (s, 3H); 13C NMR (CDCl3) δ
190.8, 160.9, 158.7, 156.4, 154.3, 147.5, 140.4, 137.5, 131.9, 130.2, 129.8,
pyrimidin-6-one (5b). Yellow solid; mp 164ꢀ166 °C; IR (KBr, cmꢀ1
)
1664, 1557, 815, 785, 716; 1H NMR (CDCl3) δ 11.64 (s, 1H),
6.84ꢀ7.39 (m, 8H), 5.51 (s, 1H), 4.08 (t, J = 5.5 Hz, 2H), 3.55 (s,
2H), 3.22ꢀ3.40 (m, 2H), 2.11ꢀ2.14 (m, 2H); 13C NMR (CDCl3) δ
192.2, 163.7, 157.9, 155.6, 143.4, 140.3, 138.2, 134.2, 132.4, 132.1, 131.4,
130 9, 129.5, 129.0, 111.6, 101.8, 43.8, 41.9, 41.3, 21.6; HRMS (ESI-
TOF, [M þ H]þ) calcd for C22H19N2O2Cl2, 413.0824, found 413.0843.
11-Chloro-benzo-1,2,3-trihydropyrido[3,2,1-ij][1,8]naphthyridine-
7-benzyl-5,8-dione (7b). White solid; mp 268ꢀ269 °C; IR (KBr, cmꢀ1
)
1668, 1621, 1596, 1576, 1509, 846, 786, 710; 1H NMR(CDCl3) δ: 8.33
(d, J = 8.5 Hz, 1H), 7.20ꢀ7.47 (m, 7H), 6.08 (s, 1H), 4.64 (s, 2H), 4.28
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(t, J = 6.0 Hz, 2H), 4.18 (t, J = 6.0 Hz, 2H), 2.33ꢀ2.38 (m, 2H); 13
C
2H), 2.08ꢀ2.13 (m, 2H), 1.61 (s, w, 2H), 1.04ꢀ1.10 (m, 4H), 0.83 (s,
2H), 0.76 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3) δ 189.5, 162.0, 154.0,
152.6, 143.6, 141.0, 132.9, 131.5, 130.4, 129.6, 129.1, 128.3, 128.0, 125.8,
116.0, 98.6, 40.1, 38.8, 32.3, 32.1, 30.6, 22.4, 19.5, 14.0; HRMS (ESI-TOF,
[M þ H]þ) calcd for C27H29N2O2Cl2, 483.1606, found 483.1615.
10-Chloro-benzo-1,2,3-trihydropyrido[3,2,1-ij][1,8]naphthyridine-
6-benzyl-7-pentyl-5,8-dione (7f). White solid; mp 169ꢀ171 °C; IR
(KBr, cmꢀ1) 1624, 1575, 806, 743, 699; 1H NMR (CDCl3) δ 8.40 (d, J =
2.0 Hz, 1H), 7.13ꢀ7.58 (m, 7H), 4.32 (t, J = 6.0 Hz, 2H), 4.21 (t, J = 6.0
Hz, 2H), 4.07 (s, 2H), 3.32 (s, w, 2H), 2.33ꢀ2.37 (m, 2H), 1.44ꢀ1.52
(m, 4H), 1.31ꢀ1.38 (m, 2H), 0.90 (t, J = 7.0 Hz, 3H); 13C NMR
(CDCl3) δ 174.4, 161.5, 153.5, 146.0, 140.6, 137.6, 132.6, 129.9, 128.4,
128.2, 126.8, 126.2, 126.0, 122.5, 116.0, 104.2, 46.3, 39.7, 32.6, 32.0, 31.5,
30.0, 22.7, 19.9, 14.2; HRMS (ESI-TOF, [M þ H]þ) calcd for
C27H28N2O2Cl, 447.1839, found 447.1818.
8-Butyl-9-(2-chlorobenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-
6-one (5g). Yellow solid; mp 139ꢀ141 °C; IR (KBr, cmꢀ1) 1665, 1571,
854, 773; 1H NMR (CDCl3) δ 11.54 (s, 1H), 7.24ꢀ7.41 (m, 4H), 5.71
(s, 1H), 4.07 (t, J = 5.0 Hz, 2H), 3.51 (t, J = 5.0 Hz, 2H), 2.07ꢀ2.11 (m,
2H), 1.84 (s, w, 2H), 1.23ꢀ1.27 (m, 2H), 0.89ꢀ0.96 (m, 2H), 0.68 (t,
J = 7.0 Hz, 3H); 13C NMR (CDCl3) δ 191.1, 161.4, 156.3, 155.2, 142.4,
131.0, 130.4, 130.2, 128.7, 126.7, 106.6, 99.0, 39.3, 38.8, 35.3, 32.0, 22.4,
19.1, 13.5; HRMS (ESI-TOF, [M þ H]þ) calcd for C19H22N2O2Cl,
345.1370, found 345.1374.
NMR (CDCl3) δ 177.3, 163.3, 157.5, 149.6, 142.6, 141.7, 141.5, 132.0,
131.4, 130.9, 128.8, 126.9, 125.7, 117.0, 116.8, 106.7, 48.7, 43.6, 41.4,
22.1; HRMS (ESI-TOF, [M þ H]þ) calcd for C22H18N2O2Cl,
377.1057, found 377.1047.
7-Benzyl-9-(2,4-dichlorobenzoyl)-8-methyl-1,2,3,4-tetra-hydropyrido
[1,2-a]pyrimidin-6-one (5c). Light yellow solid; mp 143ꢀ145 °C; IR
(KBr, cmꢀ1) 1644, 1571, 832, 812, 786, 727, 697; 1H NMR (CDCl3) δ
11.34 (s, 1H), 7.12ꢀ7.42 (m, 8H), 4.12 (s, w, 2H), 3.87 (s, 2H), 3.52 (s,
w, 2H), 2.12 (s, w, 2H), 1.63 (s, 3H); 13C NMR (CDCl3) δ 192.4, 164.0,
156.3, 150.1, 144.1, 142.9, 138.1, 134.4, 132.6, 132.1, 130.8, 130.5, 129.7,
128.2, 119.3, 102.7, 42.4, 41.1, 34.8, 23.2, 21.9; HRMS (ESI-TOF, [M þ
H]þ) calcd for C23H21N2O2Cl2, 427.0980, found 427.0974.
11-Chloro-benzo-1,2,3-trihydropyrido[3,2,1-ij][1,8]naphthyridine-
6-benzyl-7-methyl-5,8-dione (7c). White solid; mp 261ꢀ263 °C; IR
(KBr, cmꢀ1) 1624, 1594, 1574, 1511, 783, 749, 702; 1H NMR (CDCl3)
δ 8.34 (d, J = 8.5 Hz, 1H), 7.13ꢀ7.47 (m, 7H), 4.33 (t, J = 6.0 Hz, 2H),
4.19 (t, J = 6.0 Hz, 2H), 4.09 (s, 2H), 2.34ꢀ2.38 (m, 2H), 1.61 (s, 3H);
13C NMR (CDCl3) δ 177.9, 163.6, 151.6, 148.0, 142.5, 142.4, 141.5,
131.4, 130.8, 130.7, 128.4, 126.7, 126.0, 125.5, 116.8, 107.3, 48.5, 42.1, 34.8,
22.3, 22.2; HRMS (ESI-TOF, [M þ H]þ) calcd for C23H20N2O2Cl,
391.1213, found 391.1216.
7-Benzyl-9-(2,4-dichlorobenzoyl)-8-pentyl-1,2,3,4-tetrahydropyrido[1,2-
a]pyrimidin-6-one (5d). Yellow solid; mp 129ꢀ131 °C; IR (KBr, cmꢀ1
)
1635, 1575, 1567, 1538, 913, 822, 811, 784, 693; 1H NMR (CDCl3) δ 11.06
(s, 1H), 7.12ꢀ7.43 (m, 8H), 4.11 (t, J=5.5Hz, 2H), 3.89(s, 2H), 3.50(s, w,
2H), 2.07ꢀ2.14 (m, 2H), 1.62 (s, w, 2H), 1.03ꢀ1.09 (m, 4H), 0.84 (s, w,
2H), 0.75 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3) δ 190.2, 162.1, 153.8,
152.7, 141.1, 140.8, 135.9, 132.3, 130.2, 128.3, 128.0, 127.2, 125.8, 115.9, 98.8,
40.1, 38.8, 32.3, 32.0, 30.5, 22.4, 19.5, 13.9; HRMS (ESI-TOF, [M þ H]þ)
calcd for C27H29N2O2Cl2, 483.1606, found 483.1590.
Benzo-1,2,3-trihydropyrido[3,2,1-ij][1,8]naphthyridine-7-butyl-5,8-
dione (7g). White solid; mp 149ꢀ151 °C; IR (KBr, cmꢀ1) 1668, 1619,
1602, 1575, 1521, 840, 755; 1H NMR (CDCl3) δ 8.41 (dd, J1 = 8.0 Hz,
J2 = 1.5 Hz, 1H), 7.35ꢀ7.67 (m, 3H), 6.19 (s, 1H), 4.27 (t, J = 5.5 Hz, 2H),
4.23 (t, J = 5.5 Hz, 2H), 3.19 (t, J = 7.5 Hz, 2H), 2.32ꢀ2.36 (m, 2H),
1.58ꢀ1.64 (m, 2H), 1.43ꢀ1.50 (m, 2H), 0.95 (t, J = 7.0 Hz, 3H); 13C
NMR (CDCl3) δ 175.4, 161.0, 157.2, 147.0, 139.4, 132.8, 127.1, 124.8,
123.8, 114.3, 112.8, 104.2, 46.0, 38.9, 35.9, 32.2, 22.7, 19.7, 14.0; HRMS
(ESI-TOF, [M þ H]þ) calcd for C19H21N2O2, 309.1603, found 309.1595.
7-Benzyl-9-(2-chlorobenzoyl)-8-methyl-1,2,3,4-tetrahydropyrido-
[1,2-a]pyrimidin-6-one (5h). Light yellow solid; mp 131ꢀ133 °C; IR
(KBr, cmꢀ1) 1647, 1578, 770, 754, 731, 697; 1H NMR (CDCl3) δ 11.39
(s, 1H), 7.11ꢀ7.40 (m, 9H), 4.12 (t, J = 5.5 Hz, 2H), 3.87 (s, 2H), 3.52
(s, w, 2H), 2.09ꢀ2.14 (m, 2H), 1.61 (s, 3H); 13C NMR (CDCl3) δ
193.8, 164.0, 156.3, 150.5, 145.7, 143.0, 133.4, 132.7, 131.2, 130.7, 130.5,
129.3, 128.1, 119.0, 102.7, 42.4, 41.1, 34.8, 22.9, 22.0; HRMS (ESI-TOF,
[M þ H]þ) calcd for C23H22N2O2Cl, 393.1370, found 393.1385.
Benzo-1,2,3-trihydropyrido[3,2,1-ij][1,8]naphthyridine-6-benzyl-7-
11-Chloro-benzo-1,2,3-trihydropyrido[3,2,1-ij][1,8]naphthyridine-
6-benzyl-7-pentyl-5,8-dione (7d). White solid; mp 185ꢀ187 °C; IR
(KBr, cmꢀ1) 1624, 1594, 1569, 1506, 836, 784, 726; 1H NMR (CDCl3)
δ 8.39 (d, J = 8.5 Hz, 1H), 7.15ꢀ7.48 (m, 7H), 4.33 (t, J = 6.0 Hz, 2H),
4.20 (t, J = 6.0 Hz, 2H), 4.08 (s, 2H), 3.32 (s, w, 2H), 2.34ꢀ2.38 (m,
2H), 1.42ꢀ1.52 (m, 4H), 1.32ꢀ1.38 (m, 2H), 0.89 (t, J = 7.0 Hz, 3H);
13C NMR (CDCl3) δ 175.0, 161.5, 153.5, 146.1, 140.5, 139.9, 139.0,
129.2, 128.4, 128.2, 126.0, 124.2, 123.6, 122.5, 114.3, 104.3, 46.3, 39.8,
32.6, 32.0, 31.5, 30.0, 22.7, 19.9, 14.2; HRMS (ESI-TOF, [M þ H]þ)
calcd for C27H28N2O2Cl, 447.1839, found 447.1829.
8-Butyl-9-(2,5-dichlorobenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]-
pyrimidin-6-one (5e). Yellow solid; mp 148ꢀ150 °C; IR (KBr, cmꢀ1
)
methyl-5,8-dione (7h). White solid; mp 273ꢀ275 °C; IR (KBr, cmꢀ1
)
1668, 1569, 864, 825; 1H NMR (CDCl3) δ 11.56 (s, 1H), 7.25ꢀ7.36
(m, 3H), 5.74 (s, 1H), 4.08 (s, 2H), 3.54 (s, 2H), 2.09ꢀ2.13 (m, 2H),
1.88 (s, w, 2H), 1.28 (s, w, 2H), 0.97 (s, w, 2H), 0.73 (t, J = 7.5 Hz, 3H);
13C NMR (CDCl3) δ 189.1, 161.4, 155.9, 155.5, 143.7, 132.9, 131.4,
130.2, 129.3, 128.6, 107.1, 98.8, 39.4, 38.9, 35.4, 32.2, 22.6, 19.2, 13.6;
HRMS (ESI-TOF, [M þ H]þ) calcd for C19H21N2O2Cl2, 379.0980,
found 379.0978.
1634, 1625, 1602, 1575, 1517, 758, 703; 1H NMR (CDCl3) δ 8.41 (dd, J1 =
8.0 Hz, J2 = 1.5 Hz, 1H), 7.14ꢀ7.67 (m, 8H), 4.33 (t, J = 6.0 Hz, 2H), 4.24
(t, J = 6.0 Hz, 2H), 4.09 (s, 2H), 2.33ꢀ2.37 (m, 2H), 1.64 (s, 3H); 13C
NMR (CDCl3) δ 178.7, 163.8, 151.8, 147.9, 142.7, 141.7, 135.1, 130.8,
130.7, 129.6, 128.3, 127.6, 126.1, 125.0, 116.6, 107.2, 48.3, 42.1, 34.8, 22.4,
22.2; HRMS (ESI-TOF, [M þ H]þ) calcd for C23H21N2O2, 357.1603,
found 357.1607.
10-Chloro-benzo-1,2,3-trihydropyrido[3,2,1-ij][1,8]naphthyridine-
8-Butyl-9-(2,4-dichloro-5-fluorobenzoyl)-1,2,3,4-tetrahydropyrido-
[1,2-a]pyrimidin-6-one (5i). Light yellow solid; mp 167ꢀ169 °C; IR
(KBr, cmꢀ1) 1672, 1563, 878, 870, 791, 726; 1H NMR (CDCl3) δ 11.45
(s, 1H), 7.48 (d, J = 7.0 Hz, 1H), 7.08 (d, J = 7.0 Hz, 1H), 5.74 (s, 1H),
4.07 (s, w, 2H), 3.53 (s, w, 2H), 2.10 (t, J = 5.0 Hz, 2H), 1.90 (s, w, 2H),
1.30 (s, w, 2H), 0.97ꢀ1.05 (m, 2H), 0.74 (t, J = 7.0 Hz, 3H); 13C NMR
(CDCl3) δ 187.9, 161.2, 157.6, 155.4, 142.1, 131.7, 126.5, 122.7, 116.7,
116.5, 107.1, 98.5, 39.3, 38.8, 35.3, 32.0, 22.4, 19.0, 13.5; HRMS (ESI-
TOF, [M þ H]þ) calcdfor C19H20N2O2Cl2F, 397.0886, found397.0879.
10-Fluoro-11-chloro-benzo-1,2,3-trihydropyrido[3,2,1-ij][1,8]naphthyri-
dine-7-butyl-5,8-dione (7i). White solid; mp 225ꢀ227 °C; IR
7-butyl-5,8-dione (7e). White solid; mp 217ꢀ219 °C; IR (KBr, cmꢀ1
)
1663, 1624, 1580, 844, 803; 1H NMR (CDCl3) δ 8.38 (s, 1H), 7.59 (d,
J = 9.0 Hz, 1H), 7.42 (d, J = 9.0 Hz, 1H), 6.22 (s, 1H), 4.29 (t, J = 6.0 Hz,
2H), 4.23 (t, J = 6.0 Hz, 2H), 3.17 (t, J = 7.5 Hz, 2H), 2.34ꢀ2.39 (m,
2H), 1.56ꢀ1.62 (m, 2H), 1.43ꢀ1.51 (m, 2H), 0.96 (t, J = 7.0 Hz, 3H);
13C NMR (CDCl3) δ 174.2, 161.0, 157.1, 147.2, 137.9, 132.8, 130.1,
126.7, 126.1, 116.2, 113.3, 104.3, 46.4, 39.0, 36.0, 32.3, 22.8, 19.8, 14.1;
HRMS (ESI-TOF, [M þ H]þ) calcd for C19H20N2O2Cl, 343.1213,
found 343.1214.
7-Benzyl-9-(2,5-dichlorobenzoyl)-8-pentyl-1,2,3,4-tetrahydropyrido-
[1,2-a]pyrimidin-6-one (5f). Yellow solid; mp 124ꢀ126 °C; IR
(KBr, cmꢀ1) 1646, 1576, 886, 789, 702; 1H NMR (CDCl3) δ 11.16 (s,
1H), 7.12ꢀ7.34 (m, 8H), 4.11 (t, J = 5.5 Hz, 2H), 3.90 (s, 2H), 3.51 (s, w,
1
(KBr, cmꢀ1) 1661, 1632, 1607, 1581, 833, 786; H NMR (CDCl3) δ
8.11 (d, J = 7.0 Hz, 1H), 7.54 (d, J = 7.0 Hz, 1H), 6.21 (s, 1H), 4.28 (t, J =
5.5 Hz, 2H), 4.20 (t, J = 5.5 Hz, 2H), 3.14 (t, J = 7.5 Hz, 2H), 2.34ꢀ2.39
3062
dx.doi.org/10.1021/jo102167g |J. Org. Chem. 2011, 76, 3054–3063

The Journal of Organic Chemistry
ARTICLE
(m, 2H), 1.54ꢀ1.60 (m, 2H), 1.43ꢀ1.49 (m, 2H), 0.94 (t, J = 7.0 Hz,
3H); 13C NMR (CDCl3) δ 176.1, 163.2, 159.3, 158.2, 156.2, 149.7,
138.4, 130.2, 129.3, 129.1, 127.4, 119.5, 116.1, 115.8, 106.3, 49.1, 41.3,
38.3, 34.6, 25.2, 22.1, 16.5; HRMS (ESI-TOF, [M þ H]þ) calcd for
C19H19N2O2ClF, 361.1119, found 361.1120.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures; co-
b
pies of H NMR, 13C NMR, and HRMS spectra of all new
1
compounds; and X-ray data for compounds 4a and 6g in CIF
format. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: liming928@qust.edu.cn; wenlirong@qust.edu.cn.
’ ACKNOWLEDGMENT
This work was financially supported by the National Natural
Science Foundation of China (Nos. 20872074 and 21072110)
and the Natural Science Foundation of Shandong Province (Nos.
Z2008B03 and ZR2010BM007).
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