Palladium(II)-catalyzed cyclization of heterocyclic ketene aminals with (E)-ethyl 2,3-diiodoacrylates: Selective synthesis of bicyclic pyrroles and bicyclic pyridones

Article abstract of DOI:10.1016/j.tet.2014.05.032

A concise and efficient synthesis of novel bicyclic pyrroles has been achieved by PdCl₂-catalyzed cyclic condensation of six-membered heterocyclic ketene aminals (HKAs) or seven-membered HKAs with ethyl 2,3-diiodoacrylate and diethyl 2,3-diiodofumarate in the presence of Cs ₂CO₃, respectively. A series of novel bicyclic pyridones have also been obtained via five-membered HKAs with diethyl 2,3-diiodofumarate under the optimized conditions in moderate yields. These reactions are the first application of a transition metal to catalyze the building blocks HKAs to form the bicyclic pyrrole library via condensation reaction.

Full text of DOI:10.1016/j.tet.2014.05.032

Tetrahedron 70 (2014) 4478e4484
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Palladium(II)-catalyzed cyclization of heterocyclic ketene aminals
with (E)-ethyl 2,3-diiodoacrylates: selective synthesis of bicyclic
pyrroles and bicyclic pyridones
y
y
*
Ling Hu , Kai-Min Wang , Min Zhao, Xin-Rong Lin, Hong-You Zhu, Sheng-Jiao Yan ,
Jun Lin
*
Key Laboratory of Medicinal Chemistry for Natural Resources (Yunnan University), Ministry of Education, School of Chemical Science and Technology,
Yunnan University, Kunming 650091, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and efficient synthesis of novel bicyclic pyrroles has been achieved by PdCl2-catalyzed cyclic
condensation of six-membered heterocyclic ketene aminals (HKAs) or seven-membered HKAs with ethyl
2,3-diiodoacrylate and diethyl 2,3-diiodofumarate in the presence of Cs2CO3, respectively. A series of
novel bicyclic pyridones have also been obtained via five-membered HKAs with diethyl 2,3-
diiodofumarate under the optimized conditions in moderate yields. These reactions are the first appli-
cation of a transition metal to catalyze the building blocks HKAs to form the bicyclic pyrrole library via
condensation reaction.
Received 28 December 2013
Received in revised form 7 May 2014
Accepted 8 May 2014
Available online 16 May 2014
Keywords:
Bicyclic pyrroles
Bicyclic pyridones
Ó 2014 Elsevier Ltd. All rights reserved.
Heterocyclic ketene aminals
(E)-Ethyl 2,3-diiodoacrylates
1. Introduction
Pyrrole derivatives are a class of important organic compounds
and serve as key structural building blocks in numerous natural
products, synthetic biological medicinal agents, and functional
materials.1e5 As a result, more and more pyrroles have been syn-
thesized by various methods including Knorr,6 PaaleKnorr,1e,7 and
multicomponent reactions.8 Bicyclic pyrroles, one class of pyrrole
derivatives, are particularly important due to their broad spectrum
of excellent biological activities.9 Some characteristic examples of
these compounds are shown in Fig. 1, i.e., (ꢀ)-longmide B methyl
ester (with cytotoxic activity)9a and axinohydantion (which inhibits
protein kinase C).9b,10
Similarly, bicyclic pyridones represent a class of important or-
ganic molecules, which have attracted the interest of both medic-
inal and synthetic chemists. Bicyclic pyridones are core structures
in many drugs, including anti-cancer compounds11 and acetylcho-
linesterase inhibitors12,13 (Fig. 1, A58365A). Therefore, various
synthetic methods have been developed to prepare bicyclic pyr-
idones14 including [2þ2þ2] cycloaddition of alkynes and
Fig. 1. Biologically active bicyclic pyrroles and a bicyclic pyridone.
isocyanates,14aed acyl-ketene imine cyclocondensation,14e
6p-
electrocyclic ring closure,14f DielseAlder cyclization,14g rhodium-
catalyzed tandem reaction of cyclizationecycloaddition-ring
opening,14h and so on.14i,j Among them, the heterocyclic ketene
aminals (HKAs) based methods developed by the Huang15 group
have been received wide attention. However, these methods usu-
ally suffer from the use of expensive metal reagents, tedious
workup procedures, or the products lack of diversity. Hence, it is
still important to explore efficient and novel synthetic methods in
order to meet present drug discovery and high-throughput
screening needs.
HKAs are fascinating and versatile intermediates of a variety of
fused heterocyclic compounds,16 which are frequently found in
pharmacophores.17e23 However, palladium(II) catalyzed bicyclic
pyrroles formation from HKAs has not been reported. Moreover, in
* Corresponding authors. E-mail addresses: yansj@ynu.edu.cn (S.-J. Yan), linjun@
ynu.edu.cn (J. Lin).
y
The two authors contributed equally to this paper.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.032

L. Hu et al. / Tetrahedron 70 (2014) 4478e4484
4479
continuation of our research interests regarding the development
of the synthesis and applications of HKAs for new drug discovery,24
herein we report a PdCl2 catalyzed synthesis of bicyclic pyrroles
from HKAs.
satisfactory yield when using Et3N as the base, so Cs2CO3 was the
best base (Table 1, entry 18). Then, the amount of Cs2CO3 was tested
(Table 1, entries 19, 20) and it was found that the amount of base
could affect the yield of 3a. After that, the stoichiometry of sub-
strates 1a and 2a was also tested (Table 1, entries 21, 22). It was
clear that use of a 1.1:1 molar ratio of 1a/2a gave better results
(Table 1, entries 21). Finally, the model reaction was performed at
different temperatures, such as: 130 ꢁC, 70 ꢁC; or rt, and the results
suggest that the yields of 3a decreased at all of these temperatures
(Table 1, entries 23e25). Thus, the reaction conditions were opti-
mized with the presence of PdCl2 (0.1 equiv) and Cs2CO3 (1.0 equiv)
in DMSO as the solvent at 100 ꢁC.
2. Result and discussion
PdCl2-catalyzed cyclic condensation of HKAs with 2a and 2b was
investigated, respectively. The method is efficient and operationally
simple. New pyrroles 3aet were synthesized in 71e93% yields and
five new bicyclic pyridones 4aee were also constructed in 60e67%
yields.
With the optimal reaction conditions, we explored the scope
and limitations of the condensation reactions using different HKAs
and ethyl 2,3-diiodoacrylate 2a or diethyl 2,3-diiodofumarate 2b
(Table 2). First, we tested the scope of substrates 1 (Table 2, entries
1e15). Various six-membered HKAs were used to react with 2a, and
similar reactivities were observed (Table 2, entries 2e5). It is shown
that the substituents on the aromatic ring of HKAs had some in-
fluence on the yield. The substituted aromatic ring of HKAs with
electron-withdrawing groups, such as fluoro and chloro groups
(Table 2, entries 4, 5) reacted faster and gave higher yields than
those with electron-donating groups, such as methyl and methoxyl
groups (Table 2, entries 2, 3). Next, the seven-membered HKAs
(Table 2, entries 6e10) were also employed in this process, and all
reactions proceeded well, giving the corresponding bicyclic pyr-
roles 3fej. The seven-membered HKAs gave higher yields in shorter
time than six-membered HKAs, however, five-membered HKAs
1keo didn’t afford any product (Table 2, entries 11e15).
In the initial experiment, HKAs 1a and ethyl 2,3-diiodofumarate
2a were chosen as the model substrates to optimize the reaction
conditions (catalyst, base, solvent, and temperature). The results
were listed in Table 1. The reaction was not able to proceed in the
absence of catalyst (Table 1, entries 1e12, respectively). When the
catalyst PdCl2 and the base Cs2CO3 were added with EtOH as the
solvent, we obtained product 3a in 43% yield. DMSO was found to
be the best solvent, and the yield was improved to 73% (Table 1,
entry 15). Next, the reaction was performed without base and gave
lower yield (Table 1, entry 17), indicating base could efficiently
promote this reaction. However, the reaction did not give
Table 1
Optimization of the reaction conditions
In an endeavor to expand the scope of substrates 2 (Table 2,
entries 16e30), diethyl 2,3-diiodofumarate 2b was reacted with
six-membered HKAs (1aee) with both electron-withdrawing and
electron-donating groups to give bicyclic pyrroles 3keo (Table 2,
entries 16e20). Compared to ethyl 2,3-diiodoacrylate 2a, the yields
of the diethyl 2,3-diiodofumarate 2b were lower. The following
seven-membered HKAs 1fej were also employed under the opti-
mum reaction conditions with 2b to obtain similar bicyclic pyrroles
3pet in higher yields (84e90%) (Table 2, entries 21e25). Both
electron-donating and electron-withdrawing groups on aromatic
rings of HKAs were also tolerated, although the former gave slightly
reduced yields.
In order to further investigate the scope of HKAs, five-
membered HKAs 1keo were also employed to react with diethyl
2,3-diiodofunarate 2b. Surprisingly, the desired bicyclic pyrroles 3
were not obtained, instead we isolated the bicyclic pyridones 4 in
moderate yields (Table 2, entries 26e30). It is shown, the sub-
stituent on the aromatic HKAs 1keo had little influence on the
yield. However, the ring sizes are crucial to the reactions. It is easy
to fuse a six-membered ring to a five-membered ring, while the
five-membered ring of HKAs 1keo could not fuse another five-
membered ring owing to the tension of the ring, which was too
high to form bicyclic fused products.
Entry
Solvent
Catalyst
Base
T (ꢁC)
Time
(h)
Yieldh
(%)
1a
EtOH
d
d
d
d
d
d
d
d
d
d
d
d
d
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
130
rt
20
18
21
20
16
21
18
15
17
22
20
20
8
6
5
6
8
8
5
5
5
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
43
60
73
52
38
41
71
58
82
2a
Toluene
DMSO
Dioxane
EtOH
Toluene
DMSO
Dioxane
EtOH
Toluene
DMSO
Dioxane
EtOH
Toluene
DMSO
Dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
d
3a
d
4a
d
5a
Et3Ne
Et3Ne
Et3Ne
Et3Ne
CS2CO3
CS2CO3
CS2CO3
CS2CO3
CS2CO3
CS2CO3
CS2CO3
CS2CO3
d
6a
7a
8a
9a
e
e
e
e
e
e
e
e
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
20a
21b
22c
23b
24b
25b
d
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
d
d
d
d
Et3Ne
CS2CO3
CS2CO3
CS2CO3
CS2CO3
CS2CO3
CS2CO3
CS2CO3
d
d
d
d
d
d
d
d
f
To further investigate the reaction, we shortened the reaction
time (Table 2, entry 29 vs Scheme 1) and obtained a small amount
of product 4d and a large amount of the bicyclic pyridone 5a, which
contains iodine (Scheme 1). This indicated that 5a may be a pre-
cursor of 4d (Scheme 2).
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
g
e
e
e
e
e
5
5
24
8
70
61
n.r.
43
Products 3, 4, and 5a were characterized by their 1H HMR, 13
C
70
NMR, IR, and HRMS spectra, which were in agreement with the
proposed structures. We obtained a single crystal of product 3g and
the X-ray diffraction structure was shown in Fig. 2.25
Based on the above experimental results, a possible mechanism
for the formation of bicyclic pyrroles 3 is proposed and depicted in
Scheme 2. First, a small part of the HKA acts as a ligand to react with
the PdCl2 catalyst and forms a complex 6. This complex is an ef-
fective catalyst for the formation of the oxidative addition products
n.r.¼no reaction.
a
The reaction was performed with 1a (1.0 mmol), 2a (1.0 mmol).
Compounds 1a (1.1 mmol), 2a (1.0 mmol).
Compounds 1a (1.0 mmol), 2a (1.1 mmol).
PdCl2 (10 mol %).
b
c
d
e
f
Base (1.0 mmol).
Base (2.0 mmol).
Base (0.1 mmol).
Isolated yield based on 2a.
g
h

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L. Hu et al. / Tetrahedron 70 (2014) 4478e4484
Table 2
Preparation of the bicyclic pyrrole 3 or bicyclic pyridine 4a
Entry
1/n, R1
2/R2
Time (h)
3/Yieldb (%)
4/Yieldb (%)
1
2
3
4
5
6
7
8
1a/n¼1, R1¼H
1b/n¼1, R1¼CH3
1c/n¼1, R1¼OCH3
1d/n¼1, R1¼Cl
1e/n¼1, R1¼F
2a/R2¼H
5
6
6
5
4.5
5
5.5
6
4
4
8
8
9
8
11
5
6
6
5
5
5
6
6
4.5
4
6
6
6
6
3a/82
3b/81
3c/78
3d/82
3e/84
3f/89
3g/87
3h/86
3i/92
3j/93
d
d
2a/R2¼H
d
2a/R2¼H
d
2a/R2¼H
d
2a/R2¼H
d
1f/n¼2, R1¼H
2a/R2¼H
d
1g/n¼2, R1¼CH3
1h/n¼2, R1¼OCH3
1i/n¼2, R1¼Cl
1j/n¼2, R1¼F
2a/R2¼H
d
2a/R2¼H
d
9
2a/R2¼H
d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2a/R2¼H
d
1k/n¼0, R1¼H
1l/n¼0, R1¼CH3
1m/n¼0, R1¼OCH3
1n/n¼0, R1¼Cl
1o/n¼0, R1¼F
2a/R2¼H
d
2a/R2¼H
d
d
2a/R2¼H
d
d
2a/R2¼H
d
d
2a/R2¼H
d
d
1a/n¼1, R1¼H
1b/n¼1, R1¼CH3
1c/n¼1, R1¼OCH3
1d/n¼1, R1¼Cl
1e/n¼1, R1¼F
2b/R2¼COOEt
2b/R2¼COOEt
2b/R2¼COOEt
2b/R2¼COOEt
2b/R2¼COOEt
2b/R2¼COOEt
2b/R2¼COOEt
2b/R2¼COOEt
2b/R2¼COOEt
2b/R2¼COOEt
2b/R2¼COOEt
2b/R2¼COOEt
2b/R2¼COOEt
2b/R2¼COOEt
2b/R2¼COOEt
3k/74
3l/73
3m/71
3n/76
3o/77
3p/85
3q/85
3r/84
3s/90
3t/90
d
d
d
d
d
d
1f/n¼2, R1¼H
d
1g/n¼2, R1¼CH3
1h/n¼2, R1¼OCH3
1i/n¼2, R1¼Cl
1j/n¼2, R1¼F
d
d
d
d
1k/n¼0, R1¼H
1l/n¼0, R1¼CH3
1m/n¼0, R1¼OCH3
1n/n¼0, R1¼Cl
1o/n¼0, R1¼F
4a/63
4b/67
4c/60
4d/64
4e/65
d
d
d
5
d
a
The reaction was performed with 1 (1.1 mmol), 2 (1.0 mmol), PdCl2 (10 mol %), Cs2CO3 (1.0 mmol), and the solvent DMSO (10 ml) at 100 ꢁC.
Isolated yields based on 2.
b
Scheme 1. Preparation of the bicyclic pyridines.
7. Next, the HKAs 1, as aza-ene reaction components, react with
3. Conclusion
intermediates 7 to afford 8, which undergoes reductive elimination
to give intermediates 9. Then, rapid imineeenamine tautomeriza-
tion leads to the formation of 10, which again undergoes oxidative
addition with the catalyst 6 (L2Pd0) to give 11. The key in-
termediates 12 are formed by the intramolecular reaction of 11.
Finally, 12 undergoes reductive elimination to give the final prod-
ucts 3, and the complexes 6 re-enter the catalytic cycle.
A proposed mechanism of the synthesis of bicyclic pyridones 4d
is also depicted in Scheme 3. First, the five-membered HKAs 1 react
with 2b in the presence of PdCl2 and Cs2CO3 to form the in-
termediates 10, which is similar to the mechanism of bicyclic pyr-
roles 3 synthesis in Scheme 2. Then, the NH group of intermediates
10 attacks the ester intramolecularly to give the product 5a, which
is reduced to the final product 4d.
In summary, we have successfully developed a concise and ef-
ficient synthesis of novel bicyclic pyrroles and bicyclic pyridones by
cyclic condensation of HKAs with ethyl 2,3-diiodoacrylate or
diethyl 2,3-diiodofumarate in the presence of PdCl2, excess HKAs
and Cs2CO3. The ring sizes of the HKA have a significant influence
on the products. For five-membered HKAs, they can exclusively
react with diethyl 2,3-diiodofumarate to provide bicyclic pyridones,
and the yields of these reactions are not related to the substituents
of the HKAs. For the six- or seven-membered HKAs, they can react
with not only ethyl 2,3-diiodoacrylate but also diethyl 2,3-
diiodofumarate to give the corresponding bicyclic pyrroles. In ad-
dition, seven-membered HKAs and HKAs bearing electron-
withdrawing groups could provide higher yields. For the first

L. Hu et al. / Tetrahedron 70 (2014) 4478e4484
4481
Scheme 2. The possible reaction mechanism for the formation of 3.
were used as the solvent. IR spectra were recorded on an FT-IR
Thermo Nicolet Avatar 360 using KBr pellets. The reactions were
monitored by thin layer chromatography (TLC) using silica gel
GF254. The melting points were determined on an 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 using silica gel
(200e300 mesh). Compounds 1 were prepared according to the
literature.26 Compounds 2a were prepared according to the litera-
ture.27 The materials were purchased from Aldrich Corporation
Limited.
Fig. 2. X-ray crystal structure of 3g; ellipsoids are drawn at 30% probability level.
4.2. Preparation of compound 2b
Compound 2b was synthesized by the following method:28 To
a 100 ml round-bottom flask, diethyl acetylene dicarboxylate
(10.0 mmol, 1.70 g) and iodine (12.0 mmol, 3.04 g) in CHCl3 were
added. The resulting mixture was heated to reflux and stirred until
all starting acetylene was consumed, as indicated by TLC. After
cooled to rt, the reaction mixture was washed with 20% aq sodium
thiosulfate solution (40 ml) and concentrated under reduced
pressure. The residue was dissolved in ethanol (15 ml) and the
product was precipitated by the addition of water (15 ml). Re-
crystallization from methanol/water furnished a white solid 2b
(9.3 mmol, 3.95 g) in 93% yield.
4.2.1. Diethyl 2,3-diiodofunarate 2b. White solid; mp 107e109 ꢁC;
IR (KBr): 2976, 1715, 1473, 1368, 1257, 1023 cmꢀ1
;
1H NMR
(500 MHz, DMSO-d6):
d
¼1.39 (t, J¼7.0 Hz, 6H, CH3), 4.36 (q,
J¼7.0 Hz, 4H, OCH2); 13C NMR (125 MHz, DMSO-d6):
¼13.8, 63.1,
d
Scheme 3. Plausible mechanism for the formation of 4d.
87.9, 164.7; HRMS (TOF ESþ): m/z calcd for C8H10I2O4 [Mþ],
423.8668; found, 423.8658.
time, we have developed transition metal catalyzed bicyclic pyr-
roles and bicyclic pyridones synthesis and these structures are
playing unique roles in medicinal chemistry.
4.3. Typical procedure for the preparation of bicyclic pyrroles
3 and pyridones 4
4. Experimental
To a 25 ml round-bottom flask, HKAs 1 (1.1 mmol) and substrate
2 (1.0 mmol) were added to a solution of DMSO (10 ml). PdCl2
(0.1 mmol) and Cs2CO3 (1.0 mmol) were then added to the above
mixture. The resulting solution was stirred at 100 ꢁC for about
4e6 h until the substrates 2 were completely consumed. The
mixture was cooled to rt, then quenched with a saturated solution
of Na2S2O3 (20 ml) and extracted with EtOAc (50 mlꢂ3). The or-
ganic layers were combined, dried over brine and over anhydrous
4.1. General information
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 parts per mil-
lion, J values are given in hertz, and deuterated CDCl3 andDMSO-d6

4482
L. Hu et al. / Tetrahedron 70 (2014) 4478e4484
Na2SO4, concentrated, and purified by flash column chromatogra-
phy to give the products 3 or 4.
DMSO-d6):
d
¼14.5, 26.6, 28.9, 45.3, 46.9, 60.0, 105.1, 117.2, 120.2,
128.1, 128.7, 131.3, 140.1, 157.1, 160.7, 189.8; IR (KBr): 3352, 2978,
1732, 1687, 1523, 1214, 1174, 1101, 774 cmꢀ1; HRMS (ESI-TOF): m/z
calcd for C18H20N2NaO3 [(MþNa)þ], 335.1366; found, 335.1373.
4.3.1. Ethyl 8-benzoyl-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrimidine-6-
carboxylate 3a. Yellow solid; mp 120e123 ꢁC; 1H NMR (500 MHz,
DMSO-d6):
d
¼1.21 (t, J¼7.1 Hz, 3H, CH3), 1.98e2.00 (m, 2H, CH2),
4.3.7. Ethyl 9-(4-methylbenzoyl)-2,3,4,5-tetrahydro-1H-pyrrolo-[1,2-
3.30e3.48 (m, 2H, NCH2), 4.15 (q, J¼7.2 Hz, 2H, OCH2), 4.19e4.21
(m, 2H, CH2N), 6.87 (s, 1H, CH]), 7.49e7.53 (m, 3H, ArH), 7.62e7.63
(m, 2H, ArH), 7.94 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6):
a][1,3]-diazepine-7-carboxylate 3g. Yellow solid; mp 94e97 ꢁC; 1H
NMR (500 MHz, DMSO-d6):
d
¼1.19 (t, J¼7.1 Hz, 3H, CH3), 1.80e1.82
(m, 4H, CH2CH2), 2.35 (s, 3H, ArCH3), 3.27e3.29 (m, 2H, NCH2), 4.13
(q, J¼7.0 Hz, 2H, OCH2), 4.29e4.30 (m, 2H, CH2N), 6.94 (s, 1H, CH]),
7.28 (d, J¼7.8 Hz, 2H, ArH), 7.53 (d, J¼7.8 Hz, 2H, ArH), 7.91 (br, 1H,
d
¼14.7, 20.8, 37.9, 42.7, 102.8, 115.7, 118.6, 128.0, 128.7, 130.9, 140.7,
149.3, 160.5, 188.1; IR (KBr): 3352, 2973, 1695, 1618, 1534, 1348,
1165, 739 cmꢀ1; HRMS (ESI-TOF): m/z calcd for C17H19N2O3
[(MþH)þ], 299.1390; found, 299.1398.
NH); 13C NMR (125 MHz, DMSO-d6):
d
¼14.6, 21.3, 26.6, 28.9, 45.4,
46.9, 59.9, 105.2, 117.0, 120.2, 128.3, 129.3, 137.4, 141.4, 157.1, 160.7,
189.6; IR (KBr): 3300, 2922, 1689, 1601, 1208, 1091, 1174, 762 cmꢀ1
;
4.3.2. Ethyl
pyrimidine-6-carboxylate 3b. Yellow solid; mp 108e110 ꢁC; 1H
NMR (500 MHz, DMSO-d6):
8-(4-methylbenzoyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]-
HRMS (ESI-TOF): m/z calcd for C19H23N2O3 [(MþH)þ], 327.1703;
found, 327.1710.
d¼1.21 (t, J¼7.2 Hz, 3H, CH3), 1.98e2.00
(m, 2H, CH2), 2.36 (s, 3H, ArCH3), 3.36e3.38 (m, 2H, NCH2), 4.14 (q,
J¼7.1 Hz, 2H, OCH2), 4.18e4.20 (m, 2H, CH2N), 6.88 (s, 1H, CH]),
7.29 (d, J¼7.8 Hz, 2H, ArH), 7.53 (d, J¼7.9 Hz, 2H, ArH), 7.89 (br, 1H,
4.3.8. Ethyl 9-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1H-pyrrolo-
[1,2-a][1,3]-diazepine-7-carboxylate 3h. Yellow solid; mp 87e91 ꢁC;
1H NMR (500 MHz, DMSO-d6):
d
¼1.23 (t, J¼7.1 Hz, 3H, CH3),
NH); 13C NMR (125 MHz, DMSO-d6):
d¼14.7, 20.8, 21.3, 37.9, 42.7,
1.81e1.84 (m, 4H, CH2CH2), 3.29e3.31 (m, 2H, NCH2), 3.84 (s, 3H,
OCH3), 4.17 (q, J¼7.1 Hz, 2H, OCH2), 4.32e4.33 (m, 2H, CH2N), 7.00
(s, 1H, CH]), 7.05 (d, J¼8.5 Hz, 2H, ArH), 7.67 (d, J¼8.5 Hz, 2H, ArH),
59.6, 102.8, 115.6, 118.7, 128.1, 129.2, 137.9, 140.9, 149.3, 160.5, 188.0;
IR (KBr): 3348, 2975, 1690, 1612, 1539, 1219, 1168, 756 cmꢀ1; HRMS
(ESI-TOF): m/z calcd for C18H21N2O3 [(MþH)þ], 313.1547; found,
313.1556.
7.91 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6):
d
¼14.7, 26.7, 29.1,
45.5, 47.0, 55.7, 59.9, 105.2, 114.1, 116.9, 120.1, 130.4, 132.6, 157.1,
160.7, 162.0, 188.7; IR (KBr): 3300, 2921, 1688, 1600, 1431, 1228,
1169, 1090, 764 cmꢀ1; HRMS (ESI-TOF): m/z calcd for C19H22N2NaO4
[(MþNa)þ], 365.1472; found, 365.1479.
4.3.3. Ethyl 8-(4-methoxybenzoyl)-1,2,3,4-tetrahydropyrrolo-[1,2-a]
pyrimidine-6-carboxylate 3c. Yellow solid; mp 128e130 ꢁC; 1H
NMR (500 MHz, DMSO-d6):
d
¼1.22 (t, J¼7.0 Hz, 3H, CH3), 1.98e2.00
(m, 2H, CH2), 3.36e3.38 (m, 2H, NCH2), 3.82 (s, 3H, OCH3),
4.13e4.16 (m, J¼7.1 Hz, 2H, OCH2), 4.17e4.20 (m, 2H, CH2N), 6.93 (s,
1H, CH]), 7.03 (d, J¼8.6 Hz, 2H, ArH), 7.64 (d, J¼8.6 Hz, 2H, ArH),
4.3.9. Ethyl 9-(4-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-
a][1,3]-diazepine-7-carboxylate 3i. Yellow solid; mp 103e108 ꢁC; 1H
NMR (500 MHz, DMSO-d6):
d
¼1.22 (t, J¼7.1 Hz, 3H, CH3), 1.81e1.85
7.88 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6):
d
¼14.7, 20.8, 37.9,
(m, 4H, CH2CH2), 3.33e3.38 (m, 2H, NCH2), 4.16 (q, J¼7.0 Hz, 2H,
42.7, 55.7, 59.7, 102.7, 114.0, 115.5, 118.7, 149.3, 160.6, 161.6, 187.1; IR
OCH2), 4.32e4.33 (m, 2H, CH2N), 6.93 (s, 1H, CH]), 7.58 (d,
(KBr): 3352, 2978, 1732, 1687, 1523, 1214, 1101, 1024, 774 cmꢀ1
;
J¼8.0 Hz, 2H, ArH), 7.67 (d, J¼8.0 Hz, 2H, ArH), 7.96 (br, 1H, NH); 13
C
HRMS (ESI-TOF): m/z calcd for C18H20N2NaO4 [(MþNa)þ], 351.1315;
NMR (125 MHz, DMSO-d6):
d¼14.6, 26.6, 28.8, 45.3, 47.0, 60.0,
found, 351.1322.
104.9, 117.4, 119.9, 128.9, 130.1, 136.1, 138.8, 157.2, 160.6, 188.2; IR
(KBr): 3309, 2938, 1692, 1435, 1167, 1089, 845, 772 cmꢀ1; HRMS
(ESI-TOF): m/z calcd for C18H19ClN2O3 [(MþNa)þ], 369.0976; found,
369.0985.
4.3.4. Ethyl 8-(4-chlorobenzoyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]-py-
rimidine-6-carboxylate 3d. Yellow solid; mp 169e174 ꢁC; 1H NMR
(500 MHz, DMSO-d6):
d
¼1.22 (t, J¼7.0 Hz, 3H, CH3), 1.98e2.00 (m,
2H, CH2), 4.15 (q, J¼6.9 Hz, 2H, OCH2), 4.19e4.20 (m, 2H, CH2N),
6.86 (s, 1H, CH]), 7.57 (d, J¼8.1 Hz, 2H, ArH), 7.65 (d, J¼8.1 Hz, 2H,
4.3.10. Ethyl 9-(4-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-pyrrolo-[1,2-
a][1,3]-diazepine-7-carboxylate 3j. Yellow solid; mp 201e204 ꢁC;
ArH), 7.95 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6):
d
¼14.7, 20.7,
1H NMR (500 MHz, DMSO-d6):
d
¼0.99 (t, J¼7.0 Hz, 3H, CH3),
37.9, 42.7, 59.7, 102.6, 116.0, 118.3, 128.9, 129.9, 135.7, 139.2, 149.1,
160.5, 186.5; IR (KBr): 3341, 2970, 1682, 1616, 1537, 1219, 1172, 1090,
1.57e1.61 (m, 4H, CH2CH2), 3.09e3.12 (m, 2H, NCH2), 3.93 (q,
J¼6.9 Hz, 2H, OCH2), 4.09e4.10 (m, 2H, CH2N), 6.70 (s, 1H, CH]),
7.08e7.12 (m, 2H, ArH), 7.48e7.51 (m, 2H, ArH), 7.70 (br, 1H, NH);
760 cmꢀ1
; HRMS (ESI-TOF): m/z calcd for C17H17ClN2NaO3
[(MþNa)þ], 355.0820; found, 355.0826.
13C NMR (125 MHz, DMSO-d6):
d
¼14.6, 26.6, 28.9, 45.3, 47.0, 59.9,
105.0, 115.8, 117.3, 120.0, 130.9, 136.6, 157.2, 160.6, 165.0, 188.2; IR
4.3.5. Ethyl 8-(4-fluorobenzoyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]-py-
rimidine-6-carboxylate 3e. Yellow solid; mp 142e146 ꢁC; 1H NMR
(KBr): 3282, 2917, 1692, 1605, 1436, 1218, 1164, 1095, 841 cmꢀ1
;
HRMS (ESI-TOF): m/z calcd for
353.1272; found, 353.1278.
C
18H19FN2NaO3 [(MþNa)þ],
(500 MHz, DMSO-d6):
d
¼1.19 (t, J¼7.1 Hz, 3H, CH3), 1.96e1.98 (m,
2H), 4.13 (q, J¼7.2 Hz, 2H, OCH2), 4.15e4.18 (m, 2H, CH2N), 6.85 (s,
1H, CH2]), 7.28e7.31 (m, 2H, ArH), 7.67e7.70 (m, 2H, ArH), 7.91 (br,
4.3.11. Diethyl 8-benzoyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidine-
1H, NH); 13C NMR (125 MHz, DMSO-d6):
d
¼14.7, 20.8, 37.9, 42.7,
6,7-dicarboxylate 3k. Yellow solid; mp 167e169 ꢁC; 1H NMR
59.6, 102.6, 115.7, 118.4, 130.5, 137.1, 149.4, 160.5, 162.8, 164.8, 186.6;
IR (KBr): 3354, 2966, 1693, 1614, 1537, 1220, 1167, 1090, 841,
(500 MHz, DMSO-d6):
d
¼0.96 (t, J¼6.9 Hz, 3H, CH3),1.16 (t, J¼6.9 Hz,
2H, CH3), 1.99e2.02 (m, 2H), 3.36e3.39 (m, 2H, NCH2), 3.47e3.49
(m, 2H, CH2N), 4.11e4.17 (m, 4H, OCH2, OCH2), 7.38e7.45 (m, 5H,
764 cmꢀ1
; HRMS (ESI-TOF): m/z calcd for C17H17FN2NaO3
[(MþNa)þ], 339.1115; found, 339.1113.
ArH), 7.83 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6):
d¼13.7, 14.2,
20.8, 37.9, 43.0, 60.3, 60.8, 101.5, 114.2, 123.9, 127.3, 128.1, 130.5,
141.2, 148.1, 159.9, 165.0, 189.8; IR (KBr): 3352, 2978, 1730, 1621,
1526, 1271, 1174, 775 cmꢀ1; HRMS (ESI-TOF): m/z calcd for
4.3.6. Ethyl 9-benzoyl-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,3]-dia-
zepine-7-carboxylate 3f. Yellow solid; mp 88e89 ꢁC; 1H NMR
(500 MHz, DMSO-d6):
d
¼1.19 (t, J¼6.9 Hz, 3H, CH3), 1.79e1.82 (m,
C
20H22N2NaO5 [(MþNa)þ], 393.1421; found, 393.1425.
4H, CH2CH2), 3.28e3.30 (m, 2H, NCH2), 4.12 (q, J¼7.0 Hz, 2H, OCH3),
4.28e4.30 (m, 2H, CH2N), 6.86 (s,1H, CH]), 7.46e7.53 (m, 2H, ArH),
7.58e7.62 (m, 2H, ArH), 7.93 (br, 1H, NH); 13C NMR (125 MHz,
4.3.12. Diethyl 8-(4-methylbenzoyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]
pyrimidine-6,7-dicarboxylate 3l. Yellow solid; mp 184e186 ꢁC; 1H

L. Hu et al. / Tetrahedron 70 (2014) 4478e4484
4483
NMR (500 MHz, DMSO-d6):
d
¼0.98 (t, 3H, CH3), 1.18 (t, 3H, CH3),
2940, 1733, 1701, 1544, 1404, 1100, 781 cmꢀ1; HRMS (ESI-TOF): m/z
calcd for C22H26N2NaO5 [(MþNa)þ], 421.1734; found, 421.1740.
1.99e2.01 (m, 2H, CH2), 2.34 (s, 3H, ArCH3), 3.36e3.38 (m, 2H,
NCH2), 3.53e3.54 (m, 2H, CH2N), 4.13e4.17 (m, 4H, OCH2, OCH2),
7.18e7.20 (d, J¼6.2 Hz, 2H, ArH), 7.28e7.30 (d, J¼6.6 Hz, 2H, ArH),
4.3.18. Diethyl 9-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1H-pyrrolo
7.77 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6):
d¼13.7, 14.3, 20.8,
[1,2-a][1,3]diazepine-7,8-dicarboxylate
3r. Yellow solid;
mp
21.3, 37.9, 43.4, 60.2, 60.8, 101.6, 114.1, 123.9, 127.5, 128.6, 138.5,
140.5, 148.0, 159.9, 165.0, 189.7; IR (KBr): 3352, 2978, 1732, 1687,
1621, 1214, 1174, 1015, 774 cmꢀ1; HRMS (ESI-TOF): m/z calcd for
121e123 ꢁC; 1H NMR (500 MHz, DMSO-d6):
d
¼0.97 (t, J¼7.0 Hz, 3H,
CH3), 1.19 (t, J¼7.1 Hz, 3H, CH3), 1.78e1.82 (m, 4H, CH2CH2),
3.17e3.19 (m, 2H, NCH2), 3.60e3.64 (m, 2H, CH2N), 3.81 (s, 3H,
OCH3), 4.15e4.19 (m, 4H, OCH2, OCH2), 6.96 (d, J¼8.4 Hz, 2H, ArH),
7.25 (br, 1H), 7.49 (d, J¼8.3 Hz, 2H, ArH); 13C NMR (125 MHz, DMSO-
C
21H24N2NaO5 [(MþNa)þ], 407.1577; found, 407.1585.
4.3.13. Diethyl 8-(4-methoxybenzoyl)-1,2,3,4-tetrahydropyrrolo-[1,2-
d6):
d
¼13.7, 14.1, 26.5, 29.1, 46.0, 47.5, 55.8, 60.8, 60.9, 105.5, 113.6,
a]pyrimidine-6,7-dicarboxylate 3m. Yellow solid; mp 164e168 ꢁC;
117.1, 123.2, 130.2, 133.0, 154.0, 160.3, 162.2, 164.7, 190.0; IR (KBr):
3327, 2945, 1701, 1605, 1429, 1163, 1025, 791 cmꢀ1; HRMS (ESI-
TOF): m/z calcd for C22H26N2NaO6 [(MþNa)þ], 437.1683; found,
437.1690.
1H NMR (500 MHz, DMSO-d6):
d
¼1.01 (t, J¼7.0 Hz, 3H, CH3),
1.16e1.19 (t, J¼7.2 Hz, 3H, CH3), 1.99e2.01 (m, 2H, CH2),
3.34e3.37 (m, 2H, NCH2), 3.61e3.64 (m, 2H, CH2N), 3.81 (s, 3H,
OCH3), 4.12e4.17 (m, 4H, OCH2, OCH2), 6.93 (d, J¼8.1 Hz, 2H,
ArH), 7.40 (d, J¼8.1 Hz, 2H, ArH), 7.67 (br, 1H, NH); 13C NMR
4.3.19. Diethyl
[1,2-a][1,3]-diazepine-7,8-dicarboxylate 3s. Yellow solid; mp
130e133 ꢁC; 1H NMR (500 MHz, DMSO-d6):
9-(4-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-pyrrolo
(125 MHz, DMSO-d6):
d
¼13.7, 14.3, 20.9, 37.8, 43.1, 55.7, 60.2,
60.9, 101.6, 113.4, 114.0, 123.9, 129.5, 133.7, 147.8, 159.9, 161.5,
d
¼0.98 (t, J¼7.1 Hz, 3H,
189.0; IR (KBr): 3349, 2979, 1729, 1690, 1102, 1028, 785 cmꢀ1
;
CH3), 1.18 (t, J¼7.0 Hz, 3H, CH3), 1.79e1.84 (m, 4H, CH2CH2),
3.24e3.26 (m, 2H, NCH2), 3.55e3.57 (m, 2H, CH2N), 4.13e4.17 (m,
4H, OCH2, OCH2), 7.46e7.50 (m, 5H, ArH); 13C NMR (125 MHz,
HRMS (ESI-TOF): m/z calcd for
423.1527; found, 423.1537.
C
21H24N2NaO6 [(MþNa)þ],
DMSO-d6):
d
¼13.7, 14.1, 26.3, 28.7, 45.8, 47.6, 60.9, 61.0, 104.7, 117.4,
4.3.14. Diethyl 8-(4-chlorobenzoyl)-1,2,3,4-tetrahydropyrrolo-[1,2-a]
123.0, 128.4, 129.8, 136.1, 139.2, 154.6, 160.1, 164.5, 189.6; IR (KBr):
3331, 2944, 1729, 1606, 1404, 1159, 782 cmꢀ1; HRMS (ESI-TOF): m/z
calcd for C21H23ClN2NaO5 [(MþNa)þ], 441.1188; found, 441.1196.
pyrimidine-6,7-dicarboxylate 3n. Yellow solid; mp 167e172 ꢁC; 1H
NMR (500 MHz, DMSO-d6):
d
¼1.00 (m, J¼7.0 Hz, 3H, CH3), 1.16 (t,
J¼7.0 Hz, 3H, CH3), 1.99e2.01 (m, 2H, CH2), 3.50e3.57 (m, 2H,
CH2N), 4.10e4.16 (m, 4H, OCH2, OCH2), 7.38 (d, J¼7.9 Hz, 2H, ArH),
7.47 (d, J¼7.9 Hz, 2H, ArH), 7.88 (br, 1H, NH); 13C NMR (125 MHz,
4.3.20. Diethyl 9-(4-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-pyrrolo-
[1,2-a][1,3]-diazepine-7,8-dicarboxylate 3t. Yellow solid; mp
DMSO-d6):
d
¼13.7, 14.3, 20.7, 37.8, 43.0, 60.3, 61.0, 101.3, 114.5,
126e127 ꢁC; 1H NMR (500 MHz, DMSO-d6):
0.95 (t, 3H, CH3), 1.54e1.60 (m, 4H, CH2CH2), 2.98e3.10 (m, 2H,
NCH2), 3.33e3.36 (m, 2H, CH2N), 3.90e3.93 (m, 4H, OCH2, OCH2),
7.00e7.02 (m, 2H, ArH), 7.21 (br, 1H, NH), 7.28e7.31 (m, 2H, ArH);
d¼0.74 (t, 3H, CH3),
123.6, 128.2, 129.2, 135.3, 139.8, 148.2, 159.8, 165.0, 188.3; IR (KBr):
3348, 2977,1731,1689,1524,1214,1174,1100, 772 cmꢀ1; HRMS (ESI-
TOF): m/z calcd for C20H21ClN2NaO5 [(MþNa)þ], 427.1031; found,
427.1036.
13C NMR (125 MHz, DMSO-d6):
d
¼13.7, 14.1, 26.4, 28.8, 45.8, 47.6,
60.9, 61.0, 104.9, 115.2, 117.3, 123.1, 130.6, 137.1, 154.5, 160.2, 163.1,
164.6, 189.6; IR (KBr): 3328, 2940, 1707, 1604, 1237, 1098, 843,
4.3.15. Diethyl 8-(4-fluorobenzoyl)-1,2,3,4-tetrahydropyrrolo-[1,2-a]
pyrimidine-6,7-dicarboxylate 3o. Yellow solid; mp 169e171 ꢁC; 1H
789 cmꢀ1
; HRMS (ESI-TOF): m/z calcd for C21H23FN2NaO5
NMR (500 MHz, DMSO-d6):
d
¼0.99 (t, 3H, CH3), 1.15 (t, 3H, CH3),
[(MþNa)þ], 425.1483; found, 425.1476.
1.98e2.02 (m, 2H, CH2), 3.32e3.35 (m, 2H, NCH2), 3.54e3.56 (m,
2H, CH2N), 4.10e4.15 (m, 4H, OCH2, OCH2), 7.21e7.23 (m, 2H, ArH),
7.42e7.44 (m, 2H, ArH), 7.83 (br, 1H, NH); 13C NMR (125 MHz,
4.3.21. Ethyl 8-benzoyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]-pyri-
dine-7-carboxylate 4a. Yellow solid; mp 168e172 ꢁC; 1H NMR
DMSO-d6):
d
¼13.7,14.3, 20.8, 37.9, 43.1, 60.3, 61.0,101.4,114.3,115.0,
(500 MHz, DMSO-d6):
d
¼0.88 (m, J¼6.8 Hz, 3H, CH3), 3.38e3.40 (m,
123.7, 130.0, 137.7, 148.1, 159.9, 162.6, 165.0, 188.3; IR (KBr): 3327,
2979, 1617, 1524, 1409, 1173, 1102, 1075, 777 cmꢀ1; HRMS (ESI-TOF):
m/z calcd for C20H21FN2NaO5 [(MþNa)þ], 411.1327; found, 411.1328.
2H, CH2N), 3.78e3.81 (m, 2H, NCH2), 4.08 (q, J¼6.8 Hz, 2H, OCH2),
5.77 (s, H, CH]), 7.41e7.49 (m, 5H, ArH), 8.63 (br, 1H, NH); 13C NMR
(125 MHz, DMSO-d6):
d¼13.6, 43.1, 43.7, 61.6, 93.8, 106.7, 128.0,
128.6, 131.6, 140.8, 146.1, 156.5, 160.1, 166.7, 191.5; IR (KBr): 3350,
2974,1736,1667,1605,1556,1242,1042, 755 cmꢀ1; HRMS (ESI-TOF):
m/z calcd for C17H16N2NaO4 [(MþNa)þ], 335.1002; found, 335.1002.
4.3.16. Diethyl 9-benzoyl-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,3]
diazepine-7,8-dicarboxylate 3p. Yellow solid; mp 91e93 ꢁC; 1H
NMR (500 MHz, DMSO-d6):
d
¼0.93 (t, 3H, CH3), 1.16 (t, 3H, CH3),
1.78e1.82 (m, 4H, CH2CH2), 3.20e3.24 (m, 2H, NCH2), 3.46e3.47
(m, 2H, CH2N), 4.13e4.15 (m, 4H, OCH2, OCH2), 7.41e7.50 (m, 5H,
4.3.22. Ethyl 8-(4-methylbenzoyl)-5-oxo-1,2,3,5-tetrahydroimidazo
[1,2-a]pyridine-7-carboxylate 4b. Yellow solid; mp 156e159 ꢁC; 1H
ArH); 13C NMR (125 MHz, DMSO-d6):
d
¼13.6, 14.0, 26.4, 28.7, 45.8,
NMR (500 MHz, DMSO-d6):
d¼0.88 (t, J¼7.0 Hz, 3H, CH3), 2.32 (s, 3H,
47.5, 60.9, 104.9, 117.2, 123.4, 127.8, 128.3, 131.4, 140.4, 154.6, 160.2,
ArCH3), 3.41e3.45 (m, 2H, NCH2), 3.77e3.80 (m, 2H, CH2N), 4.07 (q,
J¼7.0 Hz, 2H, OCH2), 5.76 (s, 1H, CH]), 7.21 (d, J¼7.8 Hz, 2H, ArH),
7.35 (d, J¼7.9 Hz, 2H, ArH), 8.53 (br, 1H, NH); 13C NMR (125 MHz,
164.6, 191.1; IR (KBr): 3309, 1696, 1612, 1519, 1212, 1162, 698 cmꢀ1
;
HRMS (ESI-TOF): m/z calcd for C21H24N2NaO5 [(MþNa)þ], 407.1577;
found, 407.1585.
DMSO-d6):
d
¼13.5, 21.3, 43.1, 43.7, 61.6, 94.0, 106.5, 128.1, 129.1,
138.1, 141.9, 146.1, 156.4, 160.1, 166.8, 191.3; IR (KBr): 3356, 2978,
1660, 1599, 1564, 1331, 1245, 1047, 772 cmꢀ1; HRMS (ESI-TOF): m/z
calcd for C18H18N2NaO4 [(MþNa)þ], 349.1159; found, 349.1168.
4.3.17. Diethyl 9-(4-methylbenzoyl)-2,3,4,5-tetrahydro-1H-pyrrolo
[1,2-a][1,3]-diazepine-7,8-dicarboxylate 3q. Yellow solid; mp
103e107 ꢁC; 1H NMR (500 MHz, DMSO-d6):
d
¼0.93 (t, J¼7.2 Hz, 3H,
CH3), 1.17 (t, J¼6.9 Hz, 3H, CH3), 1.77e1.81 (m, 4H, CH2CH2), 2.33 (s,
3H, ArCH3), 3.17e3.19 (m, 2H, NCH2), 3.48e3.53 (m, 2H, CH2N),
4.11e4.17 (m, 4H, OCH2, OCH2), 7.20 (d, J¼7.8 Hz, 2H, ArH), 7.37 (d,
J¼8.0 Hz, 2H, ArH), 7.40 (br, 1H, NH); 13C NMR (125 MHz, DMSO-
4.3.23. Ethyl 8-(4-methoxybenzoyl)-5-oxo-1,2,3,5-tetrahydroimidazo
[1,2-a]-pyridine-7-carboxylate 4c. Yellow solid; mp 163e164 ꢁC; 1H
NMR (500 MHz, DMSO-d6):
d¼0.92 (t, J¼6.3 Hz, 3H, CH3), 3.32e3.35
(m, 2H, CH2N), 3.53e3.56 (m, 2H, NCH2), 3.80 (s, 3H, OCH3), 4.09 (q,
J¼6.3 Hz, 2H, OCH2), 5.76 (s, 1H, CH]), 6.97 (d, J¼7.3 Hz, 2H, ArH),
7.47 (d, J¼7.3 Hz, 2H, ArH), 8.44 (br, 1H, NH); 13C NMR (125 MHz,
d6):
d
¼13.6, 14.0, 21.3, 26.4, 28.9, 45.9, 47.5, 60.9, 105.2, 117.1, 123.3,
128.1, 128.8, 137.7, 141.6, 154.4, 160.3, 164.6, 190.9; IR (KBr): 3326,

4484
L. Hu et al. / Tetrahedron 70 (2014) 4478e4484
Staszak, M. A.; Udodong, U. E.; Wepsiec, J. P. Org. Process Res. Dev. 2006, 10,
DMSO-d6):
d
¼13.7, 43.1, 43.8, 55.8, 61.5, 93.8, 106.4, 113.9, 130.2,
899e904.
133.5, 146.0, 156.2, 159.8, 162.2, 166.8, 190.4; IR (KBr): 3350, 2978,
1742, 1659, 1596, 1248, 1173, 829, 780 cmꢀ1; HRMS (ESI-TOF): m/z
calcd for C18H18N2NaO5 [(MþNa)þ], 365.1108; found, 365.1112.
7. (a) Knorr, L. Chem. Ber. 1884, 17, 1635e1642; (b) Patterson, J. M. Synthesis 1976,
281e304; (c) Banik, B. K.; Banik, I.; Renteria, M.; Dasgupta, S. K. Tetrahedron Lett.
2005, 46, 2643e2645; (d) Danks, T. N. Tetrahedron Lett. 1999, 40, 3957e3960.
8. (a) Kaupp, G.; Schemeyers, J.; Kuse, A.; Atfeh, A. Angew. Chem., Int. Ed. 1999, 38,
2896e2899; (b) Tan, B.; Shi, Z.-G.; Chua, P.-J.; Li, Y.-X.; Zhong, G.-F. Angew.
Chem., Int. Ed. 2009, 48, 758e761; (c) Cadierno, V.; Gimeno, J.; Nebra, N. Chem.
dEur. J. 2007, 13, 9973e9981; (d) Lui, X.-T.; Huang, L.; Zheng, F.-J.; Zhan, Z.-P.
Adv. Synth. Catal. 2008, 350, 2778e2788; (e) Suzuki, D.; Nobe, Y.; Watai, Y.;
Tanaka, R.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127,
7474e7479.
4.3.24. Ethyl 8-(4-chlorobenzoyl)-5-oxo-1,2,3,5-tetrahydroimidazo
[1,2-a]pyridine-7-carboxylate 4d. Yellow solid; mp 183e185 ꢁC; 1H
NMR (500 MHz, DMSO-d6):
d
¼0.91 (t, J¼7.3 Hz, 3H, CH3), 3.46e3.50
(m, 2H, NCH2), 3.76e3.80 (m, 2H, CH2N), 4.08 (q, J¼7.3 Hz, 2H, OCH2),
5.78 (s,1H, CH]), 7.45e7.49 (m, 4H, ArH), 8.65 (br,1H, NH); 13C NMR
9. (a) Umeyama, A.; Ito, S.; Yuasa, E.; Arihara, S.; Yamada, T. J. Nat. Prod. 1998, 61,
1433e1434; (b) Patil, A. D.; Freyer, A. J.; Killmer, L.; Hofmann, G.; Johnson, R. K.
Nat. Prod. Lett. 1997, 9, 201e207; (c) Chari, R. V. J.; Jackel, K. A.; Bourret, L. A.;
Derr, S. M.; Tadayoni, B. M.; Mattocks, K. M.; Shah, S. A.; Liu, C.; Blattler, W. A.;
Goldmacher, V. S. Cancer Res. 1995, 55, 4079e4084; (d) Suzawa, T.; Nagamura,
S.; Saito, H.; Ohta, S.; Hanai, N.; Yamasaki, M. J. Controlled Release 2000, 69,
27e41; (e) Suzawa, T.; Nagamura, S.; Saito, H.; Ohta, S.; Hanai, N.; Yamasaki, M.
Bioorg. Med. Chem. 2000, 8, 2175e2184.
(125 MHz, DMSO-d6):
d
¼13.6, 43.2, 43.7, 61.8, 93.7,107.0,128.7,130.0,
136.4, 139.6, 145.8, 156.5, 160.1, 166.7, 190.2; IR (KBr): 3348, 2991,
1728, 1671, 1604, 1559, 1249, 1046, 772 cmꢀ1; HRMS (ESI-TOF): m/z
calcd for C17H15ClN2NaO4 [(MþNa)þ], 369.0613; found, 369.0621.
4.3.25. Ethyl 8-(4-fluorobenzoyl)-5-oxo-1,2,3,5-tetrahydroimidazo
[1,2-a]pyridine-7-carboxylate 4e. Yellow solid; mp 165e166 ꢁC; 1H
NMR (500 MHz, DMSO-d6):
10. (a) Park, S. P.; Song, Y. S.; Lee, K. J. Tetrahedron 2009, 65, 4703e4708; (b) Zhao,
L.; Tao, K.; Li, H.; Zhang, J. Tetrahedron 2011, 67, 2803e2806; (c) Ranu, B. C.; Dey,
S. S. Tetrahedron Lett. 2003, 44, 2865e2868; (d) Gangjee, A.; Yang, J.; Queener,
S. F. Bioorg. Med. Chem. 2006, 14, 8341e8351; (e) Palmer, A. M.; Munch, G.;
Berhm, C.; Zimmermann, P. J.; Buhr, W.; Feth, M. P.; Simon, W. A. Bioorg. Med.
Chem. 2008, 16, 1511e1530.
d
¼0.70 (t, J¼7.2 Hz, 3H, CH3), 3.26e3.30
(m, 2H, NCH2), 3.55e3.58 (m, 2H, CH2N), 3.85 (q, J¼7.2 Hz, 2H,
OCH2), 5.55 (s, 1H, CH]), 7.01e7.04 (m, 2H, ArH), 7.29e7.32 (m, 2H,
ArH), 8.40 (br,1H, NH); 13C NMR (125 MHz, DMSO-d6):
d
¼13.6, 43.2,
11. Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; Mcphail, A. I.; Sim, G. A. J. Am.
Chem. Soc. 1966, 88, 3888e3890.
43.7, 61.6, 93.6, 107.0, 111.5, 130.7, 137.6, 145.8, 156.5, 159.9, 163.1,
165.1, 166.7, 190.0; IR (KBr): 3352, 2988, 1667, 1601, 1240, 1182,
12. (a) Tang, X.-C.; He, X.-C.; Bai, D.-L. Drugs Future 1999, 24, 647e663; (b) Wang,
B.-S.; Wang, H.; Wei, Z.-H.; Song, Y.-Y.; Zhang, L.; Chen, H.-Z. J. Neural Transm.
2009, 116, 457e465.
13. Hunt, A.; Mynderse, S.; Samlaska, S. K.; Fukuda, D. S.; Maciak, G. M.; Kirst, H. A.;
Occolowitz, J. L.; Swartendruber, J. K.; Jones, N. D. J. Antibiot. (Tokyo) 1988, 41,
771e779.
791 cmꢀ1
; HRMS (ESI-TOF): m/z calcd for C17H15FN2NaO4
[(MþNa)þ], 353.0908; found, 353.0913.
14. (a) Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett. 2001, 3, 2117e2119; (b) Ta-
naka, K.; Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737e4739; (c) Duong, H. A.;
Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004, 126, 11438e11439; (d) Yamamoto,
Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda, S.; Nishiyama, H.; Itoh, K. J. Am.
Chem. Soc. 2005, 127, 605e613; (e) Pemberton, N.; Jakobsson, L.; Almqvist, F.
4.3.26. Ethyl 8-(4-chlorobenzoyl)-6-iodo-5-oxo-1,2,3,5-
tetrahydroimidazo[1,2-a]pyridine-7-carboxylate 5a. Yellow solid;
mp 194e196 ꢁC; 1H NMR (500 MHz, DMSO-d6):
d
¼1.08 (t, J¼7.1 Hz,
3H), 3.70e3.77 (m, 2H, NCH2), 4.12 (q, J¼7.1 Hz, 2H, OCH2),
ꢀ
Org. Lett. 2006, 8, 935e938; (f) Alajarín, M.; Ortín, M.-M.; Sanchez-Andrada, P.;
7.47e7.52 (m, 4H, ArH), 8.41 (br, 1H, NH); 13C NMR (125 MHz,
ꢀ
Vidal, A. J. Org. Chem. 2006, 71, 8126e8139; (g) Comins, D. L.; Kuethe, J. T.;
DMSO-d6):
d
¼13.6, 43.3, 45.0, 61.9, 74.4, 96.9, 128.4, 130.8, 136.7,
ꢀ
Miller, T. M.; Fevrier, F. C.; Brooks, C. A. J. Org. Chem. 2005, 70, 5221e5234; (h)
Padwa, A.; Sheehan, S. M.; Straub, C. S. J. Org. Chem. 1999, 64, 8648e8659 For
review, see; (i) Perreault, S.; Rovis, T. Chem. Soc. Rev. 2009, 38, 3149e3159; (j)
Hamama, W. S.; Zoorob, H. H. Tetrahedron 2002, 58, 6143e6162.
137.9, 150.8, 156.1, 157.9, 166.6, 189.9; IR (KBr): 3352, 3444, 1729,
1657, 1604, 1360, 1218, 1046, 686 cmꢀ1; HRMS (ESI-TOF): m/z calcd
for C17H14ClIN2NaO4 [(MþNa)þ], 494.9579; found, 494.9582.
15. (a) Huang, Z.-T.; Wang, M.-X. J. Chem. Soc., Perkin Trans. 1 1993, 1085e1090; (b)
Zhao, M.-X.; Wang, M.-X.; Huang, Z.-T. Tetrahedron 2002, 58, 1309e1316; (c)
Naito, H.; Hata, T. Tetrahedron Lett. 2008, 49, 2298e2301.
16. For review, see: (a) Huang, Z.-T.; Wang, M.-X. Heterocycles 1994, 37, 1233e1262;
(b) Huang, Z.-T.; Wang, M.-X. Prog. Nat. Sci. 1999, 11, 971e983; (c) Wang, K.-M.;
Yan, S.-J.; Lin, J. Eur. J. Org. Chem. 2014, 1129e1145.
17. (a) Tieman, C. H.; Kollmeyer, W. D.; Roman, S. A. Ger. Offen. 2,445,421, 1976;
Chem. Abstr. 1975, 83, 97297; (b) Tieman, C. H.; Kollmeyer, W. D. U.S. Patent
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U.S. Patent 4,053,623, 1977; Chem. Abstr. 1978, 88, 37796.
18. (a) Maryanoff, B. E.; Nortey, S. O.; McNally, J. J.; Sanfilippo, P. J.; Mccomsey, D. F.;
Dubinsky, B.; Shank, R. P.; Reitz, A. B. Biomed. Chem. Lett. 1999, 9, 1547e1552; (b)
Kondo, H.; Taguchi, M.; Inoue, Y.; Sakamoto, F.; Tsukamoto, G. J. Med. Chem.
1990, 33, 2012e2015.
Acknowledgements
This work was supported by Program for Changjiang Scholars
and Innovative Research Team in University (IRT13095), the Na-
tional Natural Science Foundation of China (Nos. U1202221,
21262042, 21362042, 21162037, and 81160384) and Reserve Talent
Foundation of Yunnan Province (No. 2012HB001).
References and notes
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ꢁ
ꢁ
ꢁ
a
(3g): a: 6.6323(11) A; b: 9.9091(17) A; c: 14.608(3) A;
: 71.147(2)ꢁ;
b: 79.
238(2)ꢁ;
g
: 74.744(2)ꢁ; space group Triclinic, Pꢀ1.
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