Three-component solvent-free synthesis of highly substituted bicyclic pyridines containing a ring-junction nitrogen

Article abstract of DOI:10.1039/c0gc00373e

An efficient one-pot, three-component synthesis of highly substituted bicyclic pyridines containing a ring-junction nitrogen, starting from simple and readily available materials, is described. Cyclocondensation of heterocyclic ketene aminals (HKAs), trie

Full text of DOI:10.1039/c0gc00373e

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PAPER
www.rsc.org/greenchem | Green Chemistry
Three-component solvent-free synthesis of highly substituted bicyclic
pyridines containing a ring-junction nitrogen†
Shengjiao Yan,‡ Yulan Chen,‡ Lin Liu, Nengqin He and Jun Lin*
Received 28th July 2010, Accepted 15th September 2010
DOI: 10.1039/c0gc00373e
An efficient one-pot, three-component synthesis of highly substituted bicyclic pyridines
containing a ring-junction nitrogen, starting from simple and readily available materials, is
described. Cyclocondensation of heterocyclic ketene aminals (HKAs), triethoxymethane, and
active methylene compounds by refluxing under solvent-free and catalyst-free conditions,
provided bicyclic pyridines in excellent yields.
Introduction
Nowadays, one of the pivotal areas in green chemistry is
searching for environmentally benign reaction media to replace
the commonly used organic solvents in chemical processes.1 In
this context, solvent-free processes for organic transformations
would be promising from the viewpoint of green chemistry and
sustainable development.2
Conventional step-by-step synthetic methods cannot meet the
demands of high-throughput screening,3 which constrains the
synthesis of potential therapeutic agents and drug research and
development. To meet these demands, combinatorial methods
of synthesis have been developed among which the parallel
synthesis of single compounds now plays a prominent role.
Multicomponent reactions (MCRs)4 are particularly attractive
for parallel synthesis because large arrays of compounds with
diverse substitution patterns can be prepared in one step from
relatively simple starting materials.5 MCRs have significant
advantages over classical step-by-step approaches not only from
for the synthesis of these kinds of bicyclic pyridines. The syn-
an atom economy and environmentally friendly viewpoint, but
thetic routes to these compounds have been revised in detailed
Fig. 1 The natural products and synthetic compounds of medicinal
interest that possess a bicyclic pyridine framework.
erable attention has been paid to developing efficient methods
by Hamama21 and others.22 Although various approaches for the
preparation of the bicyclic pyridines containing a ring-junction
nitrogen framework have been developed by a number of organic
or pharmaceutical chemists,23–25 the environmentally friendly
and highly selective one-pot solvent-free preparation for these
highly substituted bicyclic pyridines has rarely been studied.
Heterocyclic ketene aminals (HKAs) have been frequently
found as pharmacophores and could play important roles in
drug discovery. As a type of versatile synthetic intermediate,
HKAs have been used for the synthesis of a wide variety of het-
erocyclic and fused heterocyclic compounds,23,24 including her-
bicides, pesticides,26 anticancer agents,23 anti-anxious agents,27
antileishmanial agents28 and antibacterial and antitherapeutic
drugs.29
also because they have straightforward experimental procedures.
Bicyclic pyridines containing a ring-junction nitrogen are
a common structural motif in a wide range of natural
products and pharmacologically active molecules, such as
antiviral,6 antibacterial,7 herbicidal,8 antifungal,9 antitumor
(NSC649900 and NSC682011, Fig. 1)10 and antiulcer agents
(zolimidine, Fig. 1),11 b-amyloid formation inhibitors (zolpidem,
Fig. 1),12 ACE inhibitors (A58365A and A58365B, Fig. 1),13
human rhinovirus 3C protease inhibitors,14 a,b-peptide aggre-
gation inhibitors,15 agonists of benzodiazepine receptor,16 cal-
cium channel blockers,17 cyclin-dependent kinases inhibitors,18
GABAA receptor modulators,19 and so on.20 Therefore, consid-
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan
University), Ministry Education, School of Chemical Science and
Technology, Yunnan University, Kunming, 650091, P. R. China.
E-mail: linjun@ynu.edu.cn; Fax: +86 871 5033215; Tel: +86 871
5033215
Results and discussion
MCRs can be used to synthesize a number of drug-like
scaffold compounds in a single step, simply by varying the
reaction substrates. HKAs are rarely used in MCRs. In this
paper, we wish to report a novel method to synthesize bicyclic
pyridine derivatives 4 by refluxing HKAs 1, triethoxymethane
† Electronic supplementary information (ESI) available: General pro-
1
cedures and spectroscopic data, including copies of H and 13C NMR
spectra. CCDC reference number 784140. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0gc00373e
‡ These authors contributed equally to this paper.
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2 and active methylene compounds 3 under solvent-free and
conditions with no catalyst, forming the target compounds with
excellent yields (Table 1).
In the initial stage, an easily available starting mate-
rial, 2-(nitromethylene)imidazolidine 1a was reacted with tri-
ethoxymethane 2 and ethyl 4,4,4-trifluoro-3-oxobutanoate 3 in
one-pot, under solvent-free and catalyst-free conditions. After
refluxing for only 30 min, the reaction successfully produced
the bicyclic pyridines 4a with an excellent yield (94%) (Table 1,
entry 1). The product was carefully identified by spectroscopic
data and high-resolution mass spectroscopy.
To explore the scope and limitations of this method, HKAs
1a–o, N,O-acetals 1p–r and N,S-acetals 1s–v were used as
substrates to react with triethoxymethane 2 and ethyl 4,4,4-
trifluoro-3-oxobutanoate 3 (Table 1, entries 1–15, 16–18 and
19–22, respectively). The results demonstrated that HKAs, with
various substituents and different ring sizes, were all good
substrates for the one-pot cyclocondensation reaction (Table 1,
entries 1–15). The reactions usually took 30–60 min at reflux
until completion and gave the products with excellent yields.
To verify the structure of the product bicyclic pyridines, 4m
was selected as a representative compound and characterized by
X-ray crystallography as shown in Fig. 2 (CCDC 784140).30
Scheme 1 Proposed mechanism for the three-component reaction.
The E factors are about 0.57–0.88 for the synthesis of
compounds 4 and 6.
Preliminary results for biological activity against human
tumor cell lines32 according to the literature33 showed the target
compounds 4 possess good anticancer activities against the
K562, HL60 (see supplementary information†). It demonstrated
that this concise and environmentally friendly process has great
potential to be applied to parallel synthesis in drug discovery.
Conclusions
To summarize, we have achieved the one-pot, three-component
synthesis of highly functional bicyclic pyridines containing
a ring-junction nitrogen under solvent-free and catalyst-free
conditions. Using different types of HKAs or N,O-acetals or
N,S-acetals and different kinds of active methylene compounds,
such as 4,4,4-trifluoro-3-oxobutanoate, diethyl malonate and
ethyl 2-cyanoacetate with triethoxymethane, as building blocks,
we could construct novel libraries of highly substituted bicyclic
pyridines that make this method suitable for combinatorial and
parallel synthesis in drug discovery. Consequently, a library of
bicyclic pyridine derivatives was rapidly constructed using this
protocol. On the other hand, the generality with respect to the
substrate scope, facile accessibility to the starting materials is
also highly appealing.
Fig. 2 ORTEP diagram of ethyl 7-hydroxy-10-(4-methyl-benzoyl)-7-
(trifluoromethyl)-1,2,3,4,5,7,8,9-octahydropyrido[1,2-a]-[1,3]diazepine-
8-carboxylate (4m); ellipsoids are drawn at 30% probability level.
Experimental
General information
A proposed mechanism for the three-component reaction is
depicted in Scheme 1. Triethoxymethane 2 reacted with ethyl
4,4,4-trifluoro-3-oxobutanoate 3 to form ethyl 2-(ethoxymethyl-
ene)-4,4,4-trifluoro-3-oxobutanoate 7. Then, 7 reacted with an
HKA 1 possibly via an aza–ene31 mechanism to obtain 8.
Then, intermediate 8 removed the ethanol to give 9. Com-
pound 9 underwent a process of imine–enamine tautomeriza-
tion and cyclization to form 10. Finally, 10 formed the final
product 4.
The scope of this synthetic method was extended to other
active methylene compounds such as diethyl malonate 5a
and ethyl 2-cyanoacetate 5b. The results are summarized in
Table 2. This demonstrated that diethyl malonate 5a and ethyl
2-cyanoacetate 5b were also good substitutes in this synthetic
procedure (Table 2, entries 1–3 vs. 4–6).
All compounds were fully characterized by spectroscopic data.
The NMR spectra were recorded on a Bruker DRX500 (1H:
500 MHz, 13C: 125 MHz), chemical shifts (d) are expressed
in ppm, and J values are given in Hz, CDCl3 and DMSO-d6
were used as solvent. IR spectra were recorded on a FT-IR
Thermo Nicolet Avatar 360 using KBr pellet. The reactions were
monitored by thin layer chromatography (TLC) using silica gel
GF254. The melting points were determined on XT-4A melting
point apparatus and are uncorrected. HRMS were performed
on an Agilent LC/MSD TOF instrument. All chemicals and
solvents were used as received without further purification unless
otherwise stated. Column chromatography was performed on
silica gel (200–300 mesh). The raw materials 1a–1w were
synthesized according to the literature.34–37
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Table 1 One-pot synthesis of bicyclic pyridine derivatives 4 under solvent-free conditions
Entry
1
1
4
Time/min
30
Yield (%)a,b
94
2
41
87
3
4
35
36
90
90
5
6
33
32
93
92
7
8
34
50
92
82
9
44
45
89
89
10
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Table 1 (Contd.)
Entry
11
1
4
Time/min
40
Yield (%)a,b
91
12
13
14
59
46
45
78
81
86
15
16
40
55
88
83
17
50
84
18
19
48
39
86
89
20
34
93
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Table 1 (Contd.)
Entry
21
1
4
Time/min
33
Yield (%)a,b
91
22
30
94
a Isolated yields after silica gel chromatography. b Yield of isolated product from reaction on a 2.5 mmol scale.
General procedure
Ethyl 8-benzoyl-5-hydroxy-5-(trifluoromethyl)-1,2,3,5-tetra-
hydroimidazo[1,2-a]pyridine-6-carboxylate (4c). White solid;
HKAs derivatives 1 (2.5 mmol), triethoxymethane 2 (3 mmol)
and active methylene compounds (ethyl 4,4,4-trifluoro-3-
oxobutanoate 3 or diethyl malonate 5a or ethyl 2-cyanoacetate
5b) (3 mmol) were placed into a 25 mL round-bottom flask and
the mixture was refluxed. The resulting solution was stirred for
1–3 h until the HKAs derivatives 1 were completely consumed.
The mixture was diluted with EtOAc (50 mL ¥ 2) and quenched
with water (50 mL). The organic layer was dried by Na2SO4,
concentrated, and purified by flash column chromatography
(petroleum ether/EtOAc = 6/1) to afford product 4 or 6 with
78-94% yield. The products were further identified by FTIR,
NMR and HRMS, being in good agreement with the assigned
structures.
Mp 163–166 ◦C; IR (KBr): 3294, 2987, 1662, 1591, 1499, 1089,
1
1025, 752, 706 cm-1; H NMR (500 MHz, CDCl3): d = 1.21
(t, J = 7.0 Hz, 3H, CH3), 3.80–4.10 (m, 4H, NCH2CH2N),
4.11–4.18 (m, 2H, OCH2), 7.42–7.54 (m, 5H, PhH), 7.84 (s,
1H, CH), 7.92 (br, 1H, OH), 9.33 (br, 1H, NH); 13C HMR
(125 MHz, CDCl3): d = 14.5, 43.8, 44.2, 61.2, 84.2 (d, J =
33.8 Hz), 91.7, 97.3, 125.1 (d, J = 295.0 Hz), 128.6, 128.7,
131.0, 139.7, 143.6, 160.4, 168.8, 191.0; HRMS (TOF ES+):
m/z calcd for C18H18F3N2O4 [(M+H)+], 383.1213; found,
383.1216.
Ethyl
5-hydroxy-8-(4-methylbenzoyl)-5-(trifluoromethyl)-
1,2,3,5-tetrahydro-imidazo[1,2-a]pyridine-6-carboxylate
(4d).
White solid; Mp 168–171 ◦C; IR (KBr): 3322, 2977, 1656,
1
1582, 1498, 1401, 1309, 1083, 766 cm-1; H NMR (500 MHz,
Ethyl
5-hydroxy-8-nitro-5-(trifluoromethyl)-1,2,3,5-tetra-
CDCl3): d = 1.25 (t, J = 7.0 Hz, 3H, CH3), 2.44 (s, 3H, ArCH3),
3.85–4.19 (m, 4H, NCH2CH2N), 4.08–4.22 (m, 2H, OCH2),
7.27 (t, J = 7.6 Hz, 2H, ArH), 7.47 (d, J = 7.6 Hz, 2H, ArH),
7.90 (s, 1H, CH), 7.97 (br, 1H, OH), 9.34 (br, 1H, NH); 13C
HMR (125 MHz, CDCl3): d = 14.6, 21.9, 43.8, 43.8, 61.2, 84.2
(d, J = 33.8 Hz), 91.7, 97.1, 125.6 (d, J = 295.0 Hz), 128.9,
129.3, 136.9, 141.4, 143.7, 160.5, 168.9, 191.0; HRMS (TOF
ES+): m/z calcd for C19H20F3N2O4 [(M+H)+], 397.1370; found,
397.1372.
hydroimidazo[1,2-a]pyridine-6-carboxylate (4a). Yellow solid;
Mp 187–192 ◦C; IR (KBr): 3358, 3086, 1675, 1597, 1460, 1385,
1
1207, 1078, 763 cm-1; H NMR (500 MHz, CDCl3): d = 1.35
(t, J = 7.1 Hz, 3H, CH3), 3.92–4.16 (m, 4H, NCH2CH2N),
4.28–4.30 (m, 2H, OCH2), 7.74 (s, 1H, CH), 8.32 (br, 1H, OH),
8.36 (br, 1H, NH); 13C HMR (125 MHz, CDCl3): d = 14.5, 43.9,
44.8, 62.2, 84.5 (d, J = 35.0 Hz), 101.5, 108.9, 124.4 (d, J =
292.5 Hz), 135.6, 155.2, 168.2; HRMS (TOF ES+): m/z calcd
for C11H13F3N3O5 [(M+H)+], 324.0802; found, 324.0804.
Ethyl
5-hydroxy-8-(4-methoxybenzoyl)-5-(trifluoromethyl)-
Ethyl
8-acetyl-5-hydroxy-5-(trifluoromethyl)-1,2,3,5-tetra-
1,2,3,5-tetrahydro- imidazo[1,2-a]pyridine-6-carboxylate (4e).
hydroimidazo[1,2-a]pyridine-6-carboxylate (4b). White solid;
Mp 107–108 ◦C; IR (KBr): 3347, 2990, 1664, 1586, 1497, 1388,
1210, 1114 cm-1; 1H NMR (500 MHz, CDCl3): d = 1.35 (t, J =
7.1 Hz, 3H, CH3), 2.25 (s, 3H, COCH3), 3.81–4.00 (m, 4H,
NCH2CH2N), 4.25–4.29 (m, 2H, OCH2), 7.81 (s, 1H, CH), 7.95
(br, 1H, OH), 9.05 (br, 1H, NH); 13C HMR (125 MHz, CDCl3):
d = 14.7, 25.4, 43.6, 43.6, 61.2, 84.3 (d, J = 32.5 Hz), 92.4, 96.9,
125.0 (d, J = 293.8 Hz), 141.9, 159.3, 168.8, 192.6; HRMS (TOF
ES+): m/z C13H16F3N2O4 [(M+H)+], 321.1057; found, 321.1058.
White solid; Mp 1801–185 ◦C; IR (KBr): 3288, 2987, 1654,
1
1594, 1400, 1253, 1170, 1088, 843 cm-1; H NMR (500 MHz,
CDCl3): d = 1.24 (t, J = 7.1 Hz, 3H, CH3), 3.89 (s, 3H, OCH3),
3.88–4.07 (m, 4H, NCH2CH2N), 4.19 (q, J = 7.1 Hz, 2H,
OCH2), 6.95 (d, J = 8.5 Hz, 2H, ArH), 7.54 (d, J = 8.5 Hz, 2H,
ArH), 7.88 (s, 1H, CH), 7.97 (br, 1H, OH), 9.28 (br, 1H, NH);
13C HMR (125 MHz, CDCl3): d = 14.6, 43.5, 43.8, 55.8, 61.1,
84.2 (d, J = 33.8 Hz), 91.6, 96.8, 113.9, 125.7 (d, J = 293.8 Hz),
130.8, 132.2, 143.8, 160.5, 162.1, 168.9, 190.3; HRMS (TOF
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Table 2 One-pot synthesis of bicyclic pyridine derivatives 6 under solvent-free conditions
Entry
1
HKAs 1
5
6
Time/min
80
Yield (%)a,b
89
5a
2
3
5a
5a
80
60
90
94
4
5
5b
5b
120
180
94
95
6
5b
180
89
a Isolated yields after silica gel chromatography. b Yield of isolated product from reaction on a 2.5 mmol scale.
ES+): m/z calcd for C19H20F3N2O5 [(M+H)+], 413.1319; found,
413.1322.
141.5, 159.4, 166.8, 169.0; HRMS (TOF ES+): m/z calcd for
C14H18F3N2O5 [(M+H)+], 351.1162; found, 351.1164.
Diethyl
5-hydroxy-5-(trifluoromethyl)-1,2,3,5-tetrahydro-
Ethyl
6-hydroxy-9-nitro-6-(trifluoromethyl)-2,3,4,6-tetra-
imidazo[1,2-a]pyridine-6,8-dicarboxylate (4f). White solid; Mp
146–149 ◦C; IR (KBr): 3398, 3308, 2988, 1638, 1575, 1411, 1332,
1216, 768 cm-1; 1H NMR (500 MHz, CDCl3): d = 1.18–1.47 (m,
6H, CH3), 3.74–4.05 (m, 4H, NCH2CH2N), 4.19–4.29 (m, 4H,
OCH2), 7.83 (s, 1H, CH), 7.91 (br, 1H, OH), 8.02 (br, 1H, NH);
13C HMR (125 MHz, CDCl3): d = 14.5, 14.7, 43.5, 44.1, 60.0,
61.0, 80.5, 84.7 (q, J = 33.8 Hz), 96.2, 125.7 (q, J = 295.0 Hz),
hydro-1H-pyrido[1,2-a]pyrimidine-7-carboxylate (4g). Yellow
solid; Mp 147–151 ◦C; IR (KBr): 3182, 2982, 1668, 1607, 1539,
1474, 1370, 1018, 752 cm-1; 1H NMR (500 MHz, CDCl3):
d = 1.31 (t, J = 7.2 Hz, 3H, CH3), 1.94–1.98 (m, 1H, CH2),
2.08–2.13 (m, 1H, CH2), 3.46–3.54 (m, 2H, CH2), 3.61–3.65 (m,
1H, CH2), 3.64–3.97 (m, 1H, CH2), 4.22–4.27 (m, 2H, OCH2),
8.40 (s, 1H, CH), 8.42 (br, 1H, OH), 10.70 (br, 1H, NH); 13C
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HMR (125 MHz, CDCl3): d = 14.5, 19.7, 39.7, 40.5, 62.2, 84.4
(q, J = 33.8 Hz), 100.2, 111.3, 124.5 (q, J = 293.8 Hz), 135.9,
151.8, 168.5; HRMS (TOF ES+): m/z calcd for C12H15F3N3O5
[(M+H)+], 338.0958; found, 338.0959.
Ethyl
10-(4-chlorobenzoyl)-7-hydroxy-7-(trifluoromethyl)-
1,2,3,4,5,7,8,9-octahydropyrido[1,2-a][1,3]diazepine-8-carboxy-
late (4l). White solid; Mp 145–146 ◦C; IR (KBr): 3421,
2946, 1654, 1589, 1367, 1236, 1167, 1097, 807 cm-1: H NMR
1
(500 MHz, CDCl3): d = 1.21 (t, J = 7.0 Hz, 3H, CH3), 1.81–1.90
(m, 2H, CH2), 2.02–2.05 (m, 2H, CH2), 3.49–3.55 (m, 2H,
NCH2), 3.68–3.73 (m, 1H, NCH2), 4.15–4.20 (m, 2H, OCH2),
4.47–4.51 (m, 1H, NCH2), 7.38–7.67 (m, 4H, ArH), 7.66 (s,
1H, CH), 9.05 (br, 1H, OH), 11.59 (br, 1H, NH); 13C HMR
(125 MHz, CDCl3): d = 14.6, 25.4, 25.5, 43.5, 45.2, 61.4, 84.3 (d,
J = 32.5 Hz), 96.4, 96.7, 125.1 (d, J = 292.5 Hz), 128.7, 130.7,
137.0, 139.1, 144.0, 163.1, 169.1, 190.6; HRMS (TOF ES+): m/z
calcd for C20H21ClF3N2O4 [(M+H)+], 445.1136; found, 445.1145.
Ethyl
9-(4-chlorobenzoyl)-6-hydroxy-6-(trifluoromethyl)-
2,3,4,6-tetrahydro- 1H-pyrido[1,2-a]pyrimidine-7-carboxylate
(4h). Yellow solid; Mp 168–173 ◦C; IR (KBr): 3429, 2979,
1657, 1595, 1508, 1239, 1174, 1099, 816 cm-1; 1H NMR
(500 MHz, CDCl3): d = 1.21 (t, J = 6.9 Hz, 3H, CH3), 1.99–2.08
(m, 2H, CH2), 3.40–3.43 (m, 1H, NCH2), 3.54–3.58 (d, m, 2H,
NCH2), 3.94–3.98 (m, 1H, NCH2), 4.17 (q, J = 6.9 Hz, 2H,
OCH2), 7.4 (d, J = 8.1 Hz, 2H, ArH), 7.43 (d, J = 8.1 Hz, 2H,
ArH), 7.70 (s, 1H, CH), 8.63 (br, 1H, OH), 11.79 (br, 1H, NH);
13C HMR (125 MHz, CDCl3): d = 14.6, 20.1, 39.2, 39.9, 61.2,
84.0 (d, J = 32.5 Hz), 94.1, 95.5, 125.3 (d, J = 295.0 Hz), 128.7,
130.5, 136.7, 139.0, 143.7, 156.5, 169.0, 190.2; HRMS (TOF
ES+): m/z calcd for C19H19ClF3N2O4 [(M+H)+], 431.0980;
found, 431.0984.
Ethyl 10-benzoyl-7-hydroxy-7-(trifluoromethyl)-1,2,3,4,5,7,
8,9-octahydropyrido[1,2-a][1,3]diazepine-8-carboxylate
(4m).
White solid; Mp 119–121 ◦C; IR (KBr): 3433, 2969, 1647, 1578,
1496, 1364, 1096, 759, 699 cm-1; 1H NMR (500 MHz, CDCl3):
d = 1.18 (t, J = 7.2 Hz, 3H, CH3), 1.79–1.95 (m, 2H, CH2),
2.01–2.07 (m, 2H, CH2), 3.48–3.54 (m, 2H, NCH2), 3.67–3.72
(m, 1H, CH2), 4.10–4.16 (m, 2H, OCH2), 4.47–4.51 (m, 1H,
NCH2), 7.40–7.50 (m, 5H, PhH), 7.73 (s, 1H, CH), 9.06 (br, 1H,
OH), 11.66 (br, 1H, NH); 13C HMR (125 MHz, CDCl3): d =
14.5, 25.4, 25.5, 43.4, 45.2, 61.2,84.3 (d, J = 32.5 Hz), 96.2, 96.6,
125.1 (d, J = 292.5 Hz), 128.4, 129.2, 130.9, 140.6, 144.6, 163.2,
169.3, 192.2; HRMS (TOF ES+): m/z calcd for C20H22F3N2O4
[(M+H)+], 411.1526; found, 411.1533.
Ethyl 9-benzoyl-6-hydroxy-6-(trifluoromethyl)-2,3,4,6-tetra-
hydro-1H-pyrido[1,2-a]pyrimidine-7-carboxylate (4i). Yellow
solid; Mp 149–151 ◦C; IR (KBr): 3427, 2983, 1645, 1598, 1509,
1395, 1241, 1181, 751, 703 cm-1; 1H NMR (500 MHz, CDCl3):
d = 1.20 (t, J = 7.0 Hz, 3H, CH3), 1.99–2.08 (m, 2H, CH2),
3.41–3.45 (m, 1H, NCH2), 3.55–3.59 (m, 2H, NCH2), 3.96–3.99
(m, 1H, NCH2), 4.16 (q, J = 7.0 Hz, 2H, OCH2), 7.42–7.51 (m,
5H, PhH), 7.78 (s, 1H, CH), 8.66 (br, 1H, OH), 11.88 (br, 1H,
NH); 13C HMR (125 MHz, CDCl3): d = 14.5, 20.2, 39.2, 39.9,
61.1, 84.1 (d, J = 33.8 Hz), 94.2, 95.0, 125.4 (d, J = 295.0 Hz),
128.4, 129.0, 130.6, 140.7, 144.3, 156.6, 169.1, 191.8; HRMS
(TOF ES+): m/z calcd for C19H20F3N2O4 [(M+H)+], 397.1370;
found, 397.1369.
Ethyl
7-hydroxy-10-(4-methylbenzoyl)-7-(trifluoromethyl)-
1,2,3,4,5,7,8,9-octahydropyrido[1,2-a][1,3]diazepine-8-carboxy-
late (4n). White solid; Mp 138–139 ◦C; IR (KBr): 3427,
1
2933, 1650, 1589, 1369, 1236, 1169, 1098, 821 cm-1; H NMR
(500 MHz, CDCl3): d = 1.20 (t, J = 6.9 Hz, 3H, CH3), 1.80–1.88
(m, 2H, CH2), 2.00–2.03 (m, 2H, CH2), 2.41 (s, 3H, ArCH3),
3.46–3.52 (m, 2H, NCH2), 3.67–3.70 (m, 1H, NCH2), 4.16 (t,
J = 6.9 Hz, 2H, OCH2), 4.48–4.51 (m, 1H, NCH2), 7.22 (d,
J = 7.5 Hz, 2H, ArH), 7.40 (d, J = 7.5 Hz, 2H, ArH), 7.76 (s,
1H, CH), 9.09 (br, 1H, OH), 11.65 (br, 1H, NH); 13C HMR
(125 MHz, CDCl3): d = 14.6, 21.9, 25.4, 25.6, 43.5, 45.3, 61.2,
84.4 (q, J = 33.8 Hz), 96.0, 96.6, 125.0 (q, J = 292.5 Hz), 129.1,
129.4, 137.9, 141.3, 144.7, 163.3, 169.3, 192.2; HRMS (TOF
ES+): m/z calcd for C21H24F3N2O4 [(M+H)+], 425.1683; found,
425.1691.
Ethyl
6-hydroxy-9-(4-methylbenzoyl)-6-(trifluoromethyl)-
2,3,4,6-tetrahydro-1H -pyrido[1,2-a]pyrimidine-7-carboxylate
(4j). Yellow solid; Mp 165–170 ◦C; IR (KBr): 3374, 2984, 1651,
1601, 1503, 1373, 1236, 1176, 776 cm-1; H NMR (500 MHz,
1
CDCl3): d = 1.20 (t, J = 7.1 Hz, 3H, CH3), 1.78–2.08 (m, 2H,
CH2), 2.42 (s, 3H, ArCH3), 3.40–3.98 (m, 3H, NCH2CH2N),
4.16 (q, J = 7.1 Hz, 2H, OCH2), 7.23 (d, J = 7.8 Hz, 2H, ArH),
7.40 (d, J = 7.8 Hz, 2H, ArH), 7.81 (s, 1H, CH), 8.68 (br, 1H,
OH), 11.91 (br, 1H, NH); 13C HMR (125 MHz, CDCl3): d =
14.6, 20.2, 21.9, 39.2, 39.9, 61.1, 84.1 (q, J = 32.5 Hz), 94.2, 94.7,
125.4 (q, J = 293.8 Hz), 129.1, 129.2, 137.9, 141.0, 144.5, 156.6,
169.1, 191.7; HRMS (TOF ES+): m/z calcd for C20H22F3N2O4
[(M+H)+], 411.1526; found, 411.1525.
Ethyl 7-hydroxy-10-(4-methoxybenzoyl)-7-(trifluoromethyl)-
1,2,3,4,5,7,8,9-octahydropyrido[1,2-a][1,3]diazepine-8-carboxy-
late (4o). White solid; Mp 138–140 ◦C; IR (KBr): 3176,
Ethyl
6-hydroxy-9-(4-methoxybenzoyl)-6-(trifluoromethyl)-
1
2,3,4,6-tetrahydro-1H -pyrido[1,2-a]pyrimidine-7-carboxylate
(4k). Yellow solid; Mp: 148–150 ◦C; IR (KBr): 3428, 2980,
1645, 1597, 1506, 1372, 1249, 1173, 837 cm-1; 1H NMR
(500 MHz, CDCl3): d = 1.20–1.23 (m, 3H, CH3), 1.98–2.08 (m,
2H, CH2), 3.40–3.56 (m, 3H, NCH2CH2N), 3.87 (s, 3H, OCH3),
3.89–3.96 (m, 1H, NCH2), 4.15–4.19 (m, 2H, OCH2), 6.95 (d,
J = 6.4 Hz, 2H, ArH), 7.49 (d, J = 6.4 Hz, 2H, ArH), 7.83 (s,
1H, CH), 8.71 (br, 1H, OH), 11.88 (br, 1H, NH); 13C HMR
(125 MHz, CDCl3): d = 14.6, 20.2, 39.2, 39.9, 55.8, 61.0, 84.1 (d,
J = 32.5 Hz), 94.1, 94.4, 113.7, 125.5 (d, J = 295.0 Hz), 131.1,
133.2, 144.5., 156.5, 161.9, 169.1, 191.1; HRMS (TOF ES+): m/z
calcd for C20H22F3N2O5 [(M+H)+], 427.1475; found, 427.1473.
2945, 1652, 1595, 1494, 1366, 1164, 1031, 836 cm-1; H NMR
(500 MHz, CDCl3): d = 1.21 (t, J = 7.0 Hz, 3H, CH3), 1.78–
1.87 (m, 2H, CH2), 1.99–2.04 (m, 2H, CH2), 3.45–3.48 (m, 2H,
NCH2), 3.67–3.70 (m, 1H, NCH2), 3.86 (s, 3H, OCH3), 4.17 (q,
J = 7.0 Hz, 2H, OCH2), 4.48– 4.52 (m, 1H, NCH2), 6.93 (d,
J = 8.3 Hz, 2H, ArH), 7.49 (d, J = 8.3 Hz, 2H, ArH), 7.77 (s,
1H, CH), 9.11 (br, 1H, OH), 11.59 (br, 1H, NH); 13C HMR
(125 MHz, CDCl3): d = 14.6, 25.4, 25.6, 43.4, 45.3, 55.8, 61.2,
84.4 (d, J = 32.5 Hz), 95.7, 96.6, 113.7, 125.2 (d, J = 293.8 Hz),
131.4, 133.2, 144.8, 162.1, 163.2, 169.3, 191.5; HRMS (TOF
ES+): m/z calcd for C21H24F3N2O5 [(M+H)+], 441.1632; found,
441.1644.
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Ethyl 8-(4-chlorobenzoyl)-5-hydroxy-5-(trifluoromethyl)-3,5-
dihydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate (4p). White
solid; Mp: 156–158 ◦C; IR (KBr): 3178, 2980, 1663, 1600, 1529,
CDCl3): d = 14.5, 29.3, 50.1, 61.8, 86.2 (d, J = 33.8 Hz), 99.9,
104.1, 124.7 (d, J = 292.5 Hz), 128.7, 129.1, 131.7, 138.6,
140.8, 167.7, 168.8, 190.1; HRMS (TOF ES+): m/z calcd for
C18H17F3NO4S [(M+H)+], 400.0825; found, 400.0828.
1
1345, 1262, 1179, 843 cm-1; H NMR (500 MHz, CDCl3): d =
1.32 (t, J = 7.2 Hz, 3H, CH3), 4.03–4.08 (m, 2H, NCH2), 4.25–
4.29 (m, 2H, OCH2), 4.63–4.72 (m, 2H, OCH2), 7.37 (d, J =
8.3 Hz, 2H, ArH), 7.49 (d, J = 8.3 Hz, 2H, ArH), 7.94 (s, 1H,
CH), 8.13 (br, 1H, OH); 13C HMR (125 MHz, CDCl3): d =
14.6, 43.5, 61.9, 70.3, 85.8 (q, J = 33.8 Hz), 91.2, 99.9, 124.7
(q, J = 292.5 Hz), 128.6, 130.2, 137.6, 139.0, 142.7, 163.9,
168.7, 188.0; HRMS (TOF ES+): m/z calcd for C18H16ClF3NO5
[(M+H)+], 418.0664; found, 418.0665.
Ethyl 5-hydroxy-8-(4-methylbenzoyl)-5-(trifluoromethyl)-3,5-
dihydro-2H-thiazolo[3,2-a]pyridine-6-carboxylate (4u). Yellow
solid; Mp 122–123 ◦C; IR (KBr): 3273, 2986, 1664, 1581, 1453,
1
1248, 1176, 1102, 841 cm-1; H NMR (500 MHz, CDCl3): d =
1.25 (t, J = 6.7 Hz, 3H, CH3), 2.42 (s, 3H, ArCH3), 3.18–3.20 (m,
1H, NCH2), 3.30–3.33 (m, 1H, SCH2), 3.99–4.04 (m, 1H, SCH2),
4.22 (q, J = 6.7 Hz, 2H, OCH2), 4.32–4.36 (m, 1H, NCH2), 7.26
(d, J = 7.5 Hz, 2H, ArH), 7.51 (d, J = 7.4 Hz, 2H, ArH), 7.82
(s, 1H, CH), 8.21 (br, 1H, OH); 13C HMR (125 MHz, CDCl3):
d = 14.5, 21.9, 29.3, 50.0, 61.8, 86.2 (q, J = 33.8 Hz), 99.7, 104.2,
124.9 (q, J = 293.8 Hz), 129.3, 129.4, 135.8, 140.9, 142.3, 167.6,
168.9, 189.9; HRMS (TOF ES+): m/z calcd for C19H19F3NO4S
[(M+H)+], 414.0981; found, 414.0983.
Ethyl 5-hydroxy-8-(4-methylbenzoyl)-5-(trifluoromethyl)-3,5-
dihydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate (4q). White
solid; Mp 164–168 ◦C; IR (KBr): 3200, 2982, 1662, 1601, 1524,
1
1345, 1177, 1012, 838 cm-1; H NMR (500 MHz, CDCl3): d =
1.29 (t, J = 7.1 Hz, 3H, CH3), 2.39 (s, 3H, ArCH3), 3.98–4.03 (m,
2H, NCH2), 4.24 (d, J = 6.5 Hz, 2H, OCH2), 4.62–4.68 (m, 2H,
OCH2), 7.19 (d, J = 7.5 Hz, 2H, ArH), 7.46 (d, J = 7.5 Hz, 2H,
ArH), 7.94 (s, 1H, CH), 8.14 (br, 1H, OH); 13C HMR (125 MHz,
CDCl3): d = 14.6, 22.0, 43.5, 61.7, 70.3, 85.9 (q, J = 32.5, Hz),
91.4, 99.2, 124.8 (q, J = 293.8 Hz), 129.0, 129.1, 137.7, 142.1,
143.4, 163.8, 168.9, 189.2; HRMS (TOF ES+): m/z calcd for
C19H19F3NO5 [(M+H)+], 398.1210; found, 398.1213.
Ethyl
5-hydroxy-8-(4-methoxybenzoyl)-5-(trifluoromethyl)-
3,5-dihydro-2H-thiazolo[3,2-a]pyridine-6-carboxylate
(4v).
Yellow solid; Mp 135–137 ◦C; IR (KBr): 3214, 2993, 1657,
1
1593, 1452, 1388, 1260, 1020, 847 cm-1; H NMR (500 MHz,
CDCl3): d = 1.26 (t, J = 7.0 Hz, 3H, CH3), 3.17–3.21 (m, 1H,
NCH2), 3.30–3.34 (m, 1H, SCH2), 3.87 (s, 3H, OCH3), 3.97–4.01
(m, 1H, SCH2), 4.23 (q, J = 7.0 Hz, 2H, OCH2), 4.34–4.38 (m,
1H, NCH2), 6.97 (d, J = 8.6 Hz, 2H, ArH), 7.60 (d, J = 8.6 Hz,
2H, ArH), 7.83 (s, 1H, CH), 8.23 (br, 1H, OH); 13C HMR
(125 MHz, CDCl3): d = 14.5, 29.4, 50.0, 55.8, 61.8, 86.2 (q,
J = 33.8 Hz), 99.5, 104.1, 114.0, 124.9 (q, J = 293.8 Hz), 131.0,
131.4, 141.0, 162.7, 167.3, 168.9, 189.1; HRMS (TOF ES+): m/z
calcd for C19H19F3NO5S [(M+H)+], 430.0931; found, 430.0930.
Ethyl
5-hydroxy-8-(4-methoxybenzoyl)-5-(trifluoromethyl)-
(4r).
3,5-dihydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate
White solid; Mp 169–171 ◦C; IR (KBr): 3184, 3000, 1677, 1596,
1512, 1263, 1167, 1019, 852 cm-1; 1H NMR (500 MHz, CDCl3):
d = 1.31 (t, J = 7.2 Hz, 3H, CH3), 3.85 (s, 3H, OCH3), 4.01–4.06
(m, 2H, NCH2), 4.23–4.28 (m, 2H, OCH2), 4.63–4.70 (m, 2H,
OCH2), 6.90 (d, J = 8.6 Hz, 2H, ArH), 7.57 (d, J = 8.6 Hz,
2H, ArH), 7.95 (s, 1H, CH), 8.14 (br, 1H, OH); 13C HMR
(125 MHz, CDCl3): d = 14.6, 43.5, 55.7, 61.7, 70.2, 85.9 (q, J =
33.8 Hz), 91.3, 99.0, 113.6, 124.8 (q, J = 292.5 Hz), 131.1, 132.9,
143.5, 162.6, 163.6, 168.8, 188.3; HRMS (TOF ES+): m/z calcd
for C19H19F3NO6 [(M+H)+], 414.1159; found, 414.1157.
Ethyl 1,2,3,5-tetrahydro-8-(4-chlorobenzoyl)-5-oxoimidazo-
[1,2-a]pyridine-6-carboxylate (6a). Yellow solid; Mp 280–
◦
281 C; IR (KBr): 3494, 2981, 1727, 1568, 1224, 1171 cm-1;
1H NMR (500 MHz, CDCl3): d = 1.31 (t, J = 6.6 Hz, 3H,
CH3), 4.01–4.06 (m, 2H, NCH2), 4.25–4.28 (m, 4H, NCH2 and
OCH2), 7.45 (d, J = 7.2 Hz, 2H, ArH), 7.63 (d, J = 7.2 Hz, 2H,
ArH), 8.41 (s, 1H, CH), 8.80 (br, 1H, NH); 13C NMR (125 MHz,
CDCl3): d = 14.8, 43.6, 44.0, 61.2, 97.8, 107.4, 129.3, 130.1,
137.0, 138.1, 149.5, 158.3, 158.6, 165.2, 191.7; HRMS (TOF
ES+): m/z calcd for C17H15ClN2NaO4 [(M+Na)+], 369.0613;
found, 369.0618.
Ethyl 8-(4-chlorobenzoyl)-5-hydroxy-5-(trifluoromethiyl)-3,5-
dihydro-2H-thiazolo[3,2-a]pyridine-6-carboxylate (4s). Yellow
solid; Mp 145–148 ◦C; IR (KBr): 3262, 2983, 1664, 1590, 1453,
1
1245, 1175, 1099, 845 cm-1; H NMR (500 MHz, CDCl3): d =
1.26 (t, J = 7.0 Hz, 3H, CH3), 3.19–3.24 (m, 1H, NCH2), 3.32–
3.39 (m, 1H, SCH2), 4.00–4.06 (m, 1H, SCH2), 4.24 (q, J =
7.0 Hz, 2H, OCH2), 4.35–4.39 (m, 1H, NCH2), 7.44 (d, J =
8.1 Hz, 2H, ArH), 7.54 (d, J = 8.1 Hz, 2H, ArH), 7.73 (s, 1H,
CH), 8.20 (br, 1H, OH); 13C HMR (125 MHz, CDCl3): d = 14.5,
29.4, 50.1, 62.0, 86.2 (q, J = 33.8 Hz), 100.2, 103.8, 124.8 (q, J =
293.8 Hz), 129.0, 130.6, 137.0, 137.9, 140.3, 168.0, 168.7, 188.7;
HRMS (TOF ES+): m/z calcd for C18H16ClF3NO4S [(M+H)+],
434.0435; found, 434.0434.
Ethyl 1,2,3,5-tetrahydro-8-benzoyl-5-oxoimidazo[1,2-a]-pyri-
dine-6-carboxylate (6b). Yellow solid; Mp 234–236 ◦C; IR
(KBr): 3302, 2981, 1727, 1568, 1224, 1171, 1105 cm-1; 1H NMR
(500 MHz, CH3OD+DMSO-d6): d = 0.74 (t, J = 6.7 Hz, 3H,
CH3), 3.68–3.72 (m, 2H, NCH2), 3.77 (q, J = 6.7 Hz, 2H, OCH2),
4.02–4.10 (m, 2H, NCH2), 5.39 (s, 1H, CH), 7.18–7.30 (m, 5H,
ArH and CH); 13C NMR (125 MHz, CH3OD+DMSO-d6): d =
12.3, 41.4, 43.7, 59.2, 85.1, 105.8, 126.2, 127.5, 127.5, 139.7,
153.6, 156.2, 158.2, 166.5, 194.0; HRMS (TOF ES+): m/z calcd
for C17H16N2NaO4 [(M+Na)+], 335.1002; found, 335.1008.
Ethyl
8-benzoyl-5-hydroxy-5-(trifluoromethyl)-3,5-dihydro-
2H-thiazolo[3,2-a]pyridine-6-carboxylate (4t). Yellow solid;
Mp 129–132 ◦C; IR (KBr): 3441, 2987, 1658, 1583, 1498, 1397,
1252, 1182, 729 cm-1; 1H NMR (500 MHz, CDCl3): d = 1.23 (t,
J = 7.0 Hz, 3H, CH3), 3.19–3.23 (m, 1H, NCH2), 3.31–3.37 (m,
1H, SCH2), 3.99–4.06 (m, 1H, SCH2), 4.22 (q, J = 7.0 Hz, 2H,
OCH2), 4.33–4.37 (m, 1H, NCH2), 7.44–7.60 (m, 5H, PhH),
7.79 (s, 1H, CH), 8.19 (br, 1H, OH); 13C HMR (125 MHz,
Ethyl 1,2,3,5-tetrahydro-8-(4-methylbenzoyl)-5-oxoimid-azo-
[1,2-a]pyridine-6-carboxylate (6c). Yellow solid; Mp 203–
205 ◦C; IR (KBr): 3266, 2978, 1694, 1632, 1571, 1275, 1120 cm-1;
1H NMR (500 MHz, DMSO-d6): d = 0.86 (t, J = 6.9 Hz, 3H,
CH3), 2.32 (s, 3H, ArCH3), 3.64–3.71 (m, 2H, NCH2), 3.83 (q,
2050 | Green Chem., 2010, 12, 2043–2052
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J = 6.9 Hz, 2H, OCH2), 4.02–4.07 (m, 2H, NCH2), 5.29 (s, 1H,
CH), 7.15 (d, J = 7.3 Hz, 2H, ArH), 7.20 (d, J = 7.3 Hz, 2H,
ArH), 7.88 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6):
d = 14.0, 21.1, 42.3, 44.5, 59.9, 84.3, 107.4, 127.1, 129.2, 137.4,
138.1, 154.3, 155.2, 158.1, 167.2; HRMS (TOF ES-): m/z calcd
for C18H17N2O4 [(M-H)+], 325.1194; found, 325.1204.
5 (a) D. J. Ramo´n and M. Yus, Angew. Chem., Int. Ed., 2005, 44, 1602;
(b) M. D. Burke and S. L. Schreiber, Angew. Chem., Int. Ed., 2004,
43, 46.
6 K. S. Gudmundsson, J. D. Williams, J. C. Drach and L. B. Townsend,
J. Med. Chem., 2003, 46, 1449.
7 (a) Y. Rival, G. Grassy and G. Michael, Chem. Pharm. Bull., 1992,
40, 1170; (b) G. R. Rewankar, J. R. Matthews and R. K. Robins,
J. Med. Chem., 1975, 18, 1253.
8 H. Franke, J. Geisler, U. Hartfiel, W. Franke, G. Dorfmeister, M.
Ganzer, G. Johahann, and R. Rees, DE 4,120,108, 1991.
9 P. J. Beswick, I. B. Campbell, and A. Naylor, WO 9,631,509,
1996.
Ethyl 1,2,3,5-tetrahydro-5-imino-8-nitroimidazo[1,2-a]-pyri-
dine-6-carboxylate (6d). Yellow solid; Mp 213–216 ◦C; IR
(KBr): 3493, 2984, 1688, 1535, 1376, 600 cm-1; 1H NMR
(500 MHz, DMSO-d6): d = 1.27–1.31 (m, 3H, CH3), 3.70–4.00
(m, 4H, NCH2CH2N), 4.18–4.24 (m, 2H, OCH2), 8.41 (s,
1H, CH), 8.81 (br, 1H, NH), 11.40 (br, 1H, NH); 13C NMR
(125 MHz, DMSO-d6): d = 14.5, 45.2, 47.1, 60.7, 98.9, 114.2,
137.7, 150.8, 153,4, 165.1; HRMS (TOF ES+): m/z calcd for
C10H13N4O4 [(M+H)+], 253.0931; found, 253.0915.
10 (a) E. A. M. Badawey and T. Kappe, Eur. J. Med. Chem., 1995, 30,
ˇ
327; (b) M. Hranjec, M. Kralj, I. Piantanida, M. Sedic´, L. Suman, K.
Pavelic´ and G. Karminski-Zamola, J. Med. Chem., 2007, 50, 5696.
11 J. J. Kaminsky and A. M. Doweyko, J. Med. Chem., 1997, 40,
427.
12 S. C. Goodacre, L. J. Street, D. J. Hallett, J. M. Crawforth, S. Kelly,
A. P. Owens, W. P. Blackaby, R. T. Lewis, J. Stanley, A. J. Smith, P.
Ferris, B. Sohal, S. M. Cook, A. Pike, N. Brown, K. A. Wafford, G.
Marshall, J. L. Castro and J. R. Atack, J. Med. Chem., 2006, 49, 35.
13 A. H. Hunt, J. S. Mynderse, S. K. Samlaska, D. S. Fukuda, G. M.
Maciak, H. A. Kirst, J. L. Occolowitz, J. K. Swartzendruber and
N. D. Jones, J. Antibiot., 1988, 41, 771.
Ethyl 1,2,3,5-tetrahydro-5-imino-8-(4-chlorobenzoyl)-imida-
zo[1,2-a]pyridine-6-carboxylate (6e). Yellow solid; Mp 219–
226 ◦C; IR (KBr): 3494, 2982, 1669, 1569, 1374, 1224, 717 cm-1;
1H NMR (500 MHz, DMSO-d6): d = 1.22–1.25 (m, 3H, CH3),
3.96–4.00 (m, 2H, NCH2), 4.10-4.17 (m, 4H, NCH2 and OCH2),
7.61–7.66 (m, 4H, ArH), 7.96 (s, 1H, CH), 8.08 (br, 1H, NH),
9.69 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): d = 14.9,
43.7, 43.8, 59.5, 98.6, 117.3, 118.4, 129.0, 130.4, 136.4, 137.2,
150.5, 157.2, 167.0, 189.6; HRMS (TOF ES+): m/z calcd for
C17H17ClN3O3 [(M+H)+], 346.0953; found, 346.0974.
14 P. S. Dragovich, T. J. Prins, R. Zhou, T. O. Johnson, E. L. Brown,
F. C. Maldonado, S. A. Fuhrman, L. S. Zalman, A. K. Patick, D. A.
Matthews, X.-J. Hou, J. W. Meador, R. A. Ferre and S. T. Worland,
Bioorg. Med. Chem. Lett., 2002, 12, 733.
˚
15 V. Aberg, F. Norman, E. Chorell, A. Westermark, A. Olofsson, A. E.
Sauer-Eriksson and F. Almqvist, Org. Biomol. Chem., 2005, 3, 2817.
16 G. Trapani, M. Franco, A. Latrofa, L. Ricciardi, A. Carotti, M.
Serra, E. Sanna, G. Biggio and G. Liso, J. Med. Chem., 1999, 42,
3934.
17 P. J. Sanfilippo, M. Urbanski, J. B. Press, B. Dubinsky and J. B. Moore
Jr., J. Med. Chem., 1988, 31, 2221.
18 K. F. Byth, J. D. Culshaw, S. Green, S. Oakes and A. P. Thomas,
Bioorg. Med. Chem. Lett., 2004, 14, 2245.
Ethyl
1,2,3,5-tetrahydro-5-imino-8-benzoylimidazo[1,2-a]-
pyridine-6-carboxylate (6f). Yellow solid; Mp: 195–197 ◦C; IR
(KBr): 3494, 2985, 1652, 1536, 1374, 1231, 759 cm-1; 1H NMR
(500 MHz, DMSO-d6): d = 1.24–1.27 (m, 3H, CH3), 3.99–4.01
(m, 2H, NCH2), 4.12-4.21 (m, 4H, NCH2 and OCH2), 7.59–7.65
(m, 5H, PhH), 7.89 (s, 1H, CH), 9.12 (br, 1H, NH), 9.60 (br,
1H, NH); 13C NMR (125 MHz, DMSO-d6): d = 14.9, 43.7, 43.8,
59.5, 98.7, 117.3, 118.4, 128.4, 128.9, 131.5, 138.6, 150.4, 157.3,
167.0, 190.8; HRMS (TOF ES+): m/z calcd for C17H18N3O3
[(M+H)+], 312.1343; found, 312.1348.
19 A. C. Humphries, E. Gancia, M. T. Gilligan, S. Goodacre, D. Hallett,
K. J. Merchant and S. R. Thomas, Bioorg. Med. Chem. Lett., 2006,
16, 1518.
˚
20 H. Emtena¨s, K. Ahlin, J. S. Pinkner, S. J. Hultgren and F. Almqvist,
J. Comb. Chem., 2002, 4, 630.
21 For reviews, see: W. S. Hamama and H. H. Zoorob, Tetrahedron,
2002, 58, 6143.
22 For reviews, see: S. Perreault and T. Rovis, Chem. Soc. Rev., 2009, 38,
3149.
23 (a) S.-J. Yan, C. Huang, C.-X. Su, Y.-F. Ni and J. Lin, J. Comb. Chem.,
2010, 12, 91; (b) S.-J. Yan, C. Huang, X.-H. Zeng, R. Huang and J.
Lin, Bioorg. Med. Chem. Lett., 2010, 20, 48.
24 (a) S. J. Yan, Y.-F. Niu, R. Huang and J. Lin, Synlett., 2009, 17, 2821;
for reviews, see:; (b) Z.-T. Huang and M.-X. Wang, Heterocycles,
1994, 37, 1233; (c) Z.-T. Huang and M.-X. Wang, Prog. Natural Sci.,
1999, 11, 971.
25 (a) A.-M. Zhang, X.-L. Zheng, J.-F. Fan and W. Shen, Tetrahedron
Lett., 2010, 51, 828; (b) P. Tremmel and A. Geyer, Eur. J. Org. Chem.,
2005, 3475; (c) C. Bengtsson and F. Almqvist, J. Org. Chem., 2010,
75, 972; (d) M. Sellstedt and F. Almqvist, Org. Lett., 2009, 11, 5470.
26 C. H. Tieman, and W. D. Kollmeyer, US. Pat, 3,948,934,
1976.
Acknowledgements
We gratefully acknowledge the financial support from the
Natural Science Foundation of China (grant numbers 30860342
and 20762013) and the Natural Science Foundation of Yunnan
Province (2009CC017, 2008CD063).
27 B. E. Maryanoff, W. Ho, D. F. McComsey, A. B. Reitz, P. P. Grow,
S. O. Nortey, R. P. Shank, B. Dubinsky, R. J. Jr. Taylor and J. F.
Gardocki, J. Med. Chem., 1995, 38, 16.
28 S. N. Suryawanshi, S. Pandey, Rashmirathi, B. A. Bhatt and S. Gupta,
Eur. J. Med. Chem., 2007, 42, 511.
29 M. M. Abdelhalima, M. M. T. El-Saidib, S. T. Rabieb and G. A.
Elmegeeda, Steroids, 2007, 72, 459.
30 CCDC 784140 contains the supplementary crystallographic
data for compound 4m. The data can be obtained free of
charge from The Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif.
References
1 (a) J. Clark and D. Macquarrie, Handbook of Green Chemistry and
Technology, Blackwell Science, Oxford, 2002; (b) D. J. Adams, P. J.
Dyson and S. J. Tavener, Chemistry in Alternative Reaction Media,
John Wiley & Sons, Chichester, UK, 2004.
2 (a) A. Loupy, Top. Curr. Chem., 1999, 206, 153; (b) K. Tanaka and
F. Toda, Chem. Rev., 2000, 100, 1025.
3 W. M. Kana, M. M. Rosenman, K. Sakurai, T. M. Snyder and D. R.
Liu, Nature, 2004, 431, 545.
4 For reviews see: (a) Multicomponent Reactions, J. P. Zhu and
H. Bienayme, ed., Wiley-VCH Weinheim, Germany, 2005; (b) B.
Ganem, Acc. Chem. Res., 2009, 42, 463; (c) A. Do¨mling, Chem. Rev.,
2006, 106, 17; (d) J. D. Sunderhaus and S. F. Martin, Chem.–Eur. J.,
2009, 15, 1300; (e) N. Isambert and R. Lavilla, Chem.–Eur. J., 2008,
14, 8444.
31 J.-H. Zhang, M.-X. Wang and Z.-T. Huang, J. Chem. Soc., Perkin
Trans. 1, 1999, 2087.
32 The tumor cell lines were myeloid leukaemia (HL-60 and K562). Cis-
platin (DDP) was used as the reference drug. The tested compounds
showed moderate to excellent cellular cytotoxicity in the in vitro
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The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 2043–2052 | 2051
©

View Article Online
antitumor screening expressed by the IC50 values. (IC50 value, defined
as the concentration corresponding to 50% growth inhibition).
33 (a) D. K. Kim, D. H. Ryu, J. Y. Lee, N. Lee, Y. W. Kim, J. S. Kim,
K. Chang, G. J. Im, T. K. Kim and W. S. Choi, J. Med. Chem.,
2001, 44, 1594; (b) J. Carmichael, W. D. DeGraff, A. F. Gazdar, J. D.
Minna and J. B. Mitchell, Cancer Res., 1987, 47, 936; (c) T. Mossman,
J. Immunol. Methods, 1983, 65, 55.
M. Janowiec, Z. Zwolska and E. Augustynowicz-Kopec, Phosphorus,
Sulfur Silicon Relat. Elem., 2005, 180, 2291.
35 M.-X. Zhao, M.-X. Wang and Z.-T. Huang, Tetrahedron, 2002, 58,
1309.
36 (a) Z.-T. Huang and M.-X. Wang, Synthesis, 1992, 1273;
(b) Z.-J. Li and D. Charles, Synth. Commun., 2001, 31,
527.
34 (a) A. V. N. Reddy, S. N. Maiti, I. P. Singh and G. Micetich, Synth.
Commun., 1989, 19, 3021; (b) H. Foks, D. Pancechowska-Ksepko,
37 (a) Z.-T. Huang and P.-C. Zhang, Chem. Ber., 1989, 122, 2011; (b) Z.-
T. Huang and X. Shi, Synthesis, 1990, 162.
2052 | Green Chem., 2010, 12, 2043–2052
This journal is
The Royal Society of Chemistry 2010
©