Cascade reaction synthesis of multisubstituted bicyclic pyridone derivatives

Article abstract of DOI:10.1016/j.tet.2013.08.052

An efficient synthesis of novel bicyclic pyridone derivatives via cascade reaction of heterocyclic ketene aminals (HKAs) and 4-arylmethylene-2- phenyloxazol-5(4H)-ones in the presence of acetic acid has been established. Significantly, the protocol affords a straightforward approach to the construction of multisubstituted bicyclic pyridones in which one C-O bond was cleaved and new C-C and C-N bonds were formed in one pot under mild conditions.

Full text of DOI:10.1016/j.tet.2013.08.052

Tetrahedron 69 (2013) 9224e9236
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cascade reaction synthesis of multisubstituted bicyclic pyridone
derivatives
*
*
Xuebing Chen, Dandan Zhu, Xiaoying Wang, Shengjiao Yan , Jun Lin
Key Laboratory of Medicinal Chemistry for Natural Resources, 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:
Received 30 May 2013
Received in revised form 8 August 2013
Accepted 20 August 2013
Available online 27 August 2013
An efficient synthesis of novel bicyclic pyridone derivatives via cascade reaction of heterocyclic ketene
aminals (HKAs) and 4-arylmethylene-2-phenyloxazol-5(4H)-ones in the presence of acetic acid has been
established. Significantly, the protocol affords a straightforward approach to the construction of multi-
substituted bicyclic pyridones in which one CeO bond was cleaved and new CeC and CeN bonds were
formed in one pot under mild conditions.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Bicyclic pyridones
Cascade reaction
Heterocyclic ketene aminals
2-Phenyloxazol-5(4H)-ones
1. Introduction
To meet these demands, considerable attention has been paid
to cascade reactions.12 Cascade reactions proceed through mul-
Pyridone scaffolds are ubiquitous in a large number of natural
products and biologically active molecules.1 Among them,
substituted bicyclic pyridones possess a broad range of pharma-
cological activities, including CB2 agonists,2 (the inhibitors of al-
tiple steps in one pot and include multiple bond formations. This
is a promising strategy for the rapid and efficient construction of
functionalised architectures.13 Cascade reactions are powerful
tools in combinatorial chemistry as well as diversity-oriented
synthesis,14 and have been utilized in the construction of di-
verse chemical libraries of heterocyclic compounds.15 Those
compounds could provide applications in modern drug discovery
and development processes. Therefore, it is necessary to develop
some novel cascade reactions that could achieve the construction
of diverse combinatorial compound libraries.
dosterone synthase,3 Amyloid -peptide aggregation,4 irreversible
b
3CP,5 pilus formation in uropathogenic Escherichia coli,6,7 ACE
(A58365A & A58365B, Fig. 1)).8 Especially, which have antibacterial
(ABT-719)9 anticancer10 and anti-HIV activities.11 Hence, the syn-
thesis of bicyclic pyridones has become a valuable strategy for
discovering new bioactive compounds. Synthetic strategies that
enable an efficient and rapid preparation of these interesting
scaffolds are necessary.
Heterocyclic ketene aminals (HKAs) have been proven to be
the important building blocks in the construction of heterocyclic
systems,16 especially the condensed heterocyclic compounds17
through cascade or multi-component reactions.16,17 Reactions of
HKAs with a variety of
a,b-unsaturated compounds via aza-ene
reaction have been widely applied for the creation of diverse
heterocycles in recent years. However, such aza-ene reaction via
the cascade approach is scarcely reported.
Nowadays, many substrates, such as propiolic ester,18 diethyl
but-2-ynedioate19 -ketoesterenol tosylates20 and other biselec-
b
trophiles21 have been used as the building block to cyclo-
condense with heterocyclic ketene aminals to construct bicyclic
pyridones. But these methods usually only get the simple com-
pounds with poor diversity. This, in turn, places limitations on
the flexibility and subsequent applications of this chemistry. It is
Fig. 1. Biologically active bicyclic pyridones.
* Corresponding authors. E-mail addresses: yansj@ynu.edu.cn, linjun@ynu.e-
du.cn (J. Lin).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.052

X. Chen et al. / Tetrahedron 69 (2013) 9224e9236
9225
of great importance to explore novel synthetic methods to meet
the above-mentioned demands.
proven to be the best solvent. Based on these results, we continued
to optimise reaction conditions to further improve the chemical
yield. Subsequently, different acidic catalysts (20 mol %) were
employed for this cascade reaction (Table 1, entries 9e14). Results
showed that the whole series of acidic catalysts could promote the
reaction smoothly, while acetic acid proved to be the best (Table 1,
entries 8e14). Next, the amount of acetic acid was screened; the
results showed that a concentration of 30 mol % was the best (Table
1, entry 15). Therefore, the reaction conditions of 30 mol % acetic
acid as a catalyst at reflux in EtOH were found to be optimal for the
preparation of 5a.
Built upon our progressive endeavours in exploring novel cas-
cade reactions to synthesize highly substitute heterocyclic com-
pounds, we herein reported a novel and efficient protocol for the
synthesis of a new series of highly substituted bicyclic pyridone
derivatives via a cascade reaction of HKAs & 4-arylmethylene-2-
phenyloxazol-5(4H)-ones.
2. Result and discussion
Under the optimum conditions, we obtained different func-
tionalised bicyclic pyridones by this method. To our delight, a series
of N-(9-benzoyl-6-oxo-8-phenyl-2,3,4,6,7,8-hexahydro-1H-pyrido
[1,2-a]pyrimidin-7-yl)-benzamides 5 was obtained in good yields
(Table 2).
Our approach toward the design and development of new cas-
cade procedures involved the use of HKAs 1e3 and 4-
arylmethylene-2-phenyloxazol-5(4H)-ones 4 that contain a num-
ber of chemically distinct functionalities, which could rapidly
generate diverse bicyclic pyridone compounds. The starting mate-
To further expand the scope of applications of this cascade re-
action and to enlarge the library of bicyclic pyridones, different
substituents in the aryl groups of the starting 4-aryliene-2-
phenyloxazol-5(4H)-ones, including indole (Table 2, entries
22e26), furan (Table 2, entries 14e21), and thiophene (Table 2,
entries 9e13) groups, were examined. The successful production of
pyrido[1,2-a]pyrimidine derivatives indicated that this cascade re-
action was general for such transformations.
It is worth noting that the HKAs with electron-withdrawing
substituents (Table 2, entries 20e21) gave higher yields than
those with electron-donating substituents. However, the electronic
nature of the aryl group in the substituent 4 has a slightly impact on
the reaction yield (Table 2, entries 2 vs 6, 10 vs23). A substrate with
a more electron-donating aryl afforded a much lower yield than
a similar substrate with a less electron-rich aryl. We reasoned that
an electron-rich aryl group can decrease the electrophilicity of the
C]C bond, which reduces nucleophilic attack of the double bond.
In order to further explore the scopes and limitations of this
protocol, the subtrate 4-arylmethylene-2-phenyloxazol-5-(4H)-on-
es 4 were changed to other aryl group with fluorine and methyl
substituents (Scheme 1). Corresponding products 5 were obtained.
The results revealed that 4-arylmethylene-2-phenyloxazol-5-(4H)-
ones, with various substituents, were all good substrates for the
cascade reaction.
rial 4-arylmethylene-2-phenyloxazol-5-(4H)-ones
4 was easily
obtained by the reaction of aldehyde and hippuric acid at 110 ꢀC in
the presence of sodium acetate in the solvent of acetic anhydride.22
Building block HKAs were not commercially available, and were
prepared according to reported procedures.23
Firstly, we used HKAs 1a and 4-benzylidene-2-phenyloxazol-
5(4H)-one 4a as a simple substrates template to optimize reaction
conditions. Different organic solvents, such as dioxane, ethanol and
DMF were tested to synthesis of 5a in the presence of various in-
expensive and available catalysts at reflux (Table 1).
Table 1
Optimisation of the reaction conditions
Entry
Solvent
Catalyst (mol %)
t (ꢀC)
Time (h)
Yield (%)a
Subsequently, the substrate of HKAs 1 was also extended by using
other five-membered HKAs 2 & the seven-member HKA 3, and was
reacted with 4-arylmethylene-2-phenyloxazol-5- (4H)-ones 4 (Table
3 & Scheme 2). The reactions proceed smoothly under the same
conditions and we got the final product with moderate to good yields.
The size of heterocycles of heterocyclic ketene aminals also has
a significant impact on the reaction. Generally, six-membered HKAs
often give higher yields than five-membered ones, for example, the
yield of 6c was only 73% (Table 3, entries 3), whereas the yield of the
six-membered 5x was 75% (Table 2, entries 24).
All new compounds 5e7 were fully characterized on the basis of
1H NMR, 13C NMR spectra and high resolution mass spectra. The
structure of product 5a was further confirmed by X-ray crystallo-
graphic analysis24 CCDC 953332 (Fig. 2).
A proposed mechanism of the HOAc-catalysed cascade reaction
is described in Scheme 3. First, the carbonyl of 4-arylmethylene-2-
phenyloxazol-5(4H)-ones 4 accepts one proton to give the in-
termediate 8. The strong electron-withdrawing keto-carbonyl
1
2
3
4
5
6
7
8
EtOH
EtOH
Dioxane
Dioxane
EtOH
DMF
Dioxane
EtOH
DMF
Dioxane
EtOH
EtOH
DMF
Dioxane
EtOH
EtOH
d
rt
72
72
72
72
72
2
2
2
2
2
2
2
2
2
2
2
2
n.r.
n.r.
n.r.
n.r.
n.r.
72
36
81
27
12
Trace
12
13
12
90
d
Reflux
Reflux
Reflux
Reflux
110 ꢀC
Reflux
Reflux
110 ꢀC
Reflux
Reflux
Reflux
110 ꢀC
Reflux
Reflux
Reflux
Reflux
d
Et3N (20%)
Piperidine (20%)
HOAc (20%)
HOAc (20%)
HOAc (20%)
TFA (20%)
TFA (20%)
TFA (20%)
p-TSA(20%)
p-TSA (20%)
p-TSA (20%)
HOAc (30%)
HOAc (40%)
HOAc (50%)
9
10
11
12
13
14
15
16
17
81
69
EtOH
a
Isolated yields based on HKA1a. n.r.¼no reaction.
The results showed that no transformation occurred in the
presence of basic catalysts or without catalyst between room
temperature and the reflux temperatures in different solvents, even
with a period of 72 h (Table 1, entries 1e5). Nevertheless, when
acetic acid was added to the DMF, ethanol or dioxane, the reaction
was proceeded by heat, with the yield of 5a reaching 36% and 81%
(Table 1, entries 6e8), respectively. Previous results have revealed
that (i) acid is favoured in this cascade reaction; and (ii) ethanol was
groups at the
diamino groups of HKA, HKA 1e3 serve as a heteroene compo-
nent to react with -unsaturated compound 8 to form com-
pounds 9 via Michael addition reaction. Then an imineeenamine
tautomerization21f was followed to produce10. Then, the NH group
of intermediate 10 attacks the intramolecular carbonyl group via
a cyclisation reaction to form 11. Finally, hemiacetal 11 furnishes the
product 5e7 via ring cleavage & enoleketo tautomerism.
a-position of the HKA and the electron-donating
a,b

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X. Chen et al. / Tetrahedron 69 (2013) 9224e9236
Table 2
Cascade reaction synthesis of products 5 from various of 1 and 4
Entry
1
4
5
Yield (%)a
1
90
2
88
3
85
4
84
5
84
82
6

X. Chen et al. / Tetrahedron 69 (2013) 9224e9236
9227
Table 2 (continued )
Entry
1
4
5
Yield (%)a
7
82
8
80
9
79
10
79
11
80
12
79
13
79
(continued on next page)

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X. Chen et al. / Tetrahedron 69 (2013) 9224e9236
Table 2 (continued )
Entry
1
4
5
Yield (%)a
14
79
15
80
16
80
17
79
76
79
77
18
19
20

X. Chen et al. / Tetrahedron 69 (2013) 9224e9236
9229
Table 2 (continued )
Entry
1
4
5
Yield (%)a
21
76
22
75
23
74
24
75
25
73
26
73
a
Isolated yield based on HKA1.

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X. Chen et al. / Tetrahedron 69 (2013) 9224e9236
melting points were determined on XT-4A melting point appa-
ratus 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
(200e300 mesh).
4.2. Typical procedure for the preparation of bicyclic pyr-
idone 5e7
A mixture of HKAs 1e3 (0.22 g, 1 mmol) andarylmethylene-2-
phenyloxazol-5(4H)-ones
4 (0.25 g, 1 mmol), acetic acid
(0.3 mmol) and ethanol (15 mL) was stirred at reflux. Upon com-
pletion, monitored by TLC, the reaction mixture was cooled to room
temperature and concentrated in vacuo. The residue was purified
by flash chromatography (petroleum ether/ethyl acetate¼3:2),
which was further purified by recrystallization from mixed EtOAc/
CHCl3 to give pure bicyclic pyridones 5e7.
4.2.1. N-(9-(4-Fluorobenzoyl)-6-oxo-8-phenyl2,3,4,6,7,8-hexahy-
dro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzamide 5a. White solid; mp
122e124 ꢀC; IR (KBr): 3422, 3060, 1704, 1610, 1238, 1156, 715,
567 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
¼12.81 (br, 1H, NH),
7.62e7.66 (m, 2H, ArH), 7.45e7.48 (m, 1H, ArH), 7.33e7.42 (m, 2H,
ArH), 7.22e7.25 (m, 2H, ArH), 7.02e7.06 (m, 2H, ArH), 6.85e6.89
(m, 4H, ArH), 6.51 (br, 1H, NH), 5.20e5.24 (m, 1H, CH), 4.32 (d,
J¼6.4 Hz, 1H, CH), 4.11e4.15 (m, 1H, NCH2), 3.55e3.70 (m, 3H,
NCH2), 2.13e2.17 (m, 2H, CH2); 13C NMR (125 MHz, CDCl3):
d
¼190.7, 168.1, 167.1, 162.8 (d, J¼246.0 Hz), 155.6, 139.0, 137.7,
133.8, 131.9, 128.7, 128.6, 128.4, 128.3, 127.6, 127.0, 114.9 (d,
J¼21.0 Hz), 114.7 (d, J¼21.0 Hz), 90.4, 54.9, 41.7, 39.7, 38.7, 21.0;
HRMS (TOF ESþ): m/z calcd for C28H24FN3NaO3 [(MþNa)þ],
492.1694; found, 492.1696.
Scheme 1. Synthesis of bicyclic pyridones.
4.2.2. N-(9-(4-Chlorobenzoyl)-6-oxo-8-phenyl-2,3,4,6,7,8-hexahy-
dro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzamide 5b. White solid;
mp 129e131 ꢀC; IR (KBr): 3787, 3420, 1705, 1657, 1611, 1244,
913, 567 cmꢁ1
;
1H NMR (500 MHz, CDCl3):
d
¼12.82 (br, 1H,
NH), 7.66 (d, J¼6.8 Hz, 2H, ArH), 7.47e7.50 (m, 1H, ArH),
7.40e7.43 (m, 2H, ArH), 7.22e7.30 (m, 3H, ArH), 7.16e7.20 (m,
2H, ArH), 6.99 (d, J¼7.3 Hz, 2H, ArH), 6.85e6.93 (m, 2H, ArH),
6.54 (br, 1H, NH), 5.22e5.26 (m, 1H, CH), 4.31 (d, J¼5.6 Hz, 1H,
CH), 4.13e4.17 (m, 1H, NCH2), 3.53e3.77 (m, 3H, NCH2),
3. Conclusion
In conclusion, we have successfully demonstrated a novel,
efficient, economical, and environmentally friendly method for
the synthesis of a series of highly functional bicyclic pyridones
via a cascade reaction. The reaction showed that the synthetic
route allowed the construction of bicyclic pyridone derivatives
with a wide diversity of substituents as important building
blocks. Features of this strategy include the mild condition,
simple starting material, and excellent yield. Most importantly,
this series of pyrido[1,2-a]pyrimidin and imidazo[1,2-a]pyridine
derivatives may provide new classes of biologically active
compounds for biomedical screening. Further investigations
into the in vitro biological activities of compound 5e7 are in
progress.
2.14e2.22 (m, 2H, CH2); 13C NMR (125 MHz, CDCl3):
d
¼190.8,
168.4, 167.5, 156.0, 140.3, 139.4, 135.0, 134.2, 132.3, 129.2, 129.0,
128.7, 128.5, 128.2, 128.0, 127.4, 90.8, 55.3, 42.1, 40.1, 39.1, 21.3;
HRMS (TOF ESþ): m/z calcd for C28H25ClN3O3 [(MþH)þ],
486.1579; found, 486.1584.
4.2.3. N-(9-Benzoyl-6-oxo-8-phenyl-2,3,4,6,7,8-hexahydro-1H-pyr-
ido[1,2-a]pyrimidin-7-yl)benzamide
119e120 ꢀC; IR (KBr): 3832, 3425, 1701, 1658, 1614, 1244, 1163,
706 cmꢁ1; 1H NMR (500 MHz, CDCl3):
5c. White
solid;
mp
d
¼12.86 (br, 1H, NH), 7.65 (d,
J¼7.5 Hz, 2H, ArH), 7.47e7.51 (m, 1H, ArH), 7.37e7.41 (m, 2H, ArH),
7.24e7.30 (m, 4H, ArH), 7.18e7.23 (m, 3H, ArH), 7.04 (d, J¼7.4 Hz,
2H, ArH), 6.85e6.88 (m, 2H, ArH), 6.48 (br, 1H, NH), 5.25e5.28 (m,
1H, CH), 4.33 (d, J¼6.5 Hz, 1H, CH), 4.13e4.18 (m, 1H, NCH2),
3.54e3.77 (m, 3H, NCH2), 2.16e2.20 (m, 2H, CH2); 13C NMR
4. Experimental
4.1. General information
(125 MHz, CDCl3):
d
¼192.5, 168.6, 167.5, 155.8, 142.0, 139.6, 134.3,
All compounds were fully characterised by spectroscopic data.
The NMR spectra were recorded on a Bruker DRX500 or DRX400,
chemical shifts (d) are expressed in parts per million, and J values
132.2, 129.1, 128.7, 128.7, 128.3, 127.9, 127.4, 126.6, 90.8, 55.2, 42.2,
40.1, 39.1, 21.4; HRMS (TOF ESþ): m/z calcd for C28H26N3O3
[(MþH)þ], 452.1969; found, 452.1969.
are given in Hertz, and deuterated CDCl3 and DMSO-d6 were used
as solvent. IR spectra were recorded on an FT-IR Thermo Nicolet
Avatar 360 using KBr pellet. The reactions were monitored by
thin layer chromatography (TLC) using silica gel GF254. The
4.2.4. N-(9-(4-Methylbenzoyl)-6-oxo-8-phenyl-2,3,4,6,7,8-hex-ahy-
dro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzamide 5d. White solid; mp
117e120 ꢀC; IR (KBr): 3722, 3418, 1704, 1611, 1523, 1327, 1161,

X. Chen et al. / Tetrahedron 69 (2013) 9224e9236
9231
Table 3
Cascade reaction synthesis of products 3 from various of 1 and 2
Entry
1
2
4
Yield (%)a
1
77
76
73
2
3
4
73
5
72
a
Isolated yield based on HKA2.
712 cmꢁ1; 1H NMR (500 MHz, CDCl3):
J¼7.5 Hz, 2H, ArH), 7.47e7.51 (m, 1H, ArH), 7.37e7.41 (m, 2H, ArH),
7.25e7.29 (m, 3H, ArH), 6.99e7.03 (m, 2H, ArH), 6.95e6.98 (m, 2H,
ArH), 6.89e6.92 (m, 1H, ArH), 6.52 (br, 1H, NH), 5.23e5.27 (m, 1H,
d
¼12.89 (br, 1H, NH), 7.66 (d,
CH), 4.38 (d, J¼7.4 Hz, 1H, CH), 4.12e4.17 (m, 1H, NCH2), 3.55e3.72
(m, 3H, NCH2), 2.30 (s, 3H, CH3), 2.14e2.17 (m, 2H, CH2); 13C NMR
(125 MHz, CDCl3):
d¼192.0, 168.1, 167.0, 155.3, 139.2, 138.7, 138.5,
133.9, 131.7, 128.5, 128.4, 127.3, 126.9, 126.2, 124.6, 90.3, 54.7, 43.5,

9232
X. Chen et al. / Tetrahedron 69 (2013) 9224e9236
41.7, 39.6, 38.5, 21.2, 21.0; HRMS (TOF ESþ): m/z calcd for
C
29H27N3NaO3 [(MþNa)þ], 488.1945; found, 488.1947.
4.2.5. N-(9-(4-Methoxybenzoyl)-6-oxo-8-phenyl-2,3,4,6,7,8-hex-
ahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzamide 5e. White solid;
mp 111e114 ꢀC; IR (KBr): 3792, 3412, 1608, 1525, 1246, 1167, 837,
714 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d
¼12.90 (br, 1H, NH), 7.68 (d,
J¼7.5 Hz, 2H, ArH), 7.49e7.52 (m, 1H, ArH), 7.39e7.43 (m, 2H, ArH),
7.24e7.30 (m, 3H, ArH), 7.04e7.08 (m, 2H, ArH), 6.90e6.96 (m, 2H,
ArH), 6.72 (d, J¼8.2 Hz, 2H, ArH), 6.54 (br, 1H, NH), 5.23e5.27 (m,
1H, CH), 4.43 (d, J¼6.1 Hz, 1H, CH), 4.14e4.19 (m, 1H, NCH2), 3.78 (s,
3H, OCH3), 3.54e3.75 (m, 3H, NCH2), 2.16e2.20 (m, 2H, CH2); 13C
Scheme 2. Synthesis of bicyclic pyridone 7.
NMR (125 MHz, CDCl3):
d
¼192.0, 168.6, 167.5, 160.5, 155.8, 139.7,
134.7, 134.3, 132.2, 129.1, 129.0, 128.8, 128.5, 127.8, 127.4, 113.5, 90.8,
55.6, 55.3, 42.3, 40.1, 39.1, 21.5; HRMS (TOF ESþ): m/z calcd for
C
29H28N3O4 [(MþH)þ], 482.2074; found, 482.2078.
4.2.6. N-(9-(4-Chlorobenzoyl)-8-(4-methoxyphenyl)-6-oxo-
2,3,4,6,7,8-hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzamide
5f. White solid; mp 114e117 ꢀC; IR (KBr): 3775, 3426, 1706, 1655,
1613, 1245, 1171, 802 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d
¼12.64
(br, 1H, NH), 7.74 (d, J¼7.6 Hz, 2H, ArH), 7.68 (br, 1H, NH), 7.50e7.54
(m, 1H, ArH), 7.40e7.45 (m, 2H, ArH), 7.29 (d, J¼8.1 Hz, 1H, ArH),
6.99 (d, J¼8.1 Hz, 2H, ArH), 6.80e6.84 (m, 2H, ArH), 6.74e6.78 (m,
2H, ArH), 5.17e5.21 (m, 1H, CH), 4.09 (d, J¼6.2 Hz, 1H, CH),
3.95e4.01 (m, 1H, NCH2), 3.76 (s, 3H, OCH3), 3.60e3.70 (m, 3H,
NCH2), 2.06e2.09 (m, 2H, CH2); 13C NMR (125 MHz, DMSO-d6):
d
¼187.6, 168.0, 166.7, 158.6, 156.1, 141.2, 134.0, 133.4, 132.0, 131.6,
129.6, 128.8, 128.2, 128.1, 127.7, 114.3, 90.3, 55.4, 55.3, 40.7, 39.8,
38.6, 20.4; HRMS (TOF ESþ): m/z calcd for C29H27ClN3O4 [(MþH)þ],
516.1685; found, 516.1686.
4.2.7. N-(9-Benzoyl-8-(4-methoxyphenyl)-6-oxo-2,3,4,6,7,8-hex-
ahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzamide 5g. White solid;
mp 120e124 ꢀC; IR (KBr): 3730, 3420, 1614, 1512, 1380, 1164, 902,
Fig. 2. X-ray crystal structures of 5a; ellipsoids are drawn at 30% probability level.
711 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d
¼12.70 (br, 1H, NH), 7.73
(d, J¼7.3 Hz, 1H, ArH), 7.67 (br, 1H, NH), 7.50e7.53 (m, 1H, ArH),
7.40e7.44 (m, 2H, ArH), 7.28e7.30 (m, 1H, ArH), 7.20e7.24 (m, 2H,
ArH), 6.96e6.99 (m, 2H, ArH), 6.79e6.81 (m, 2H, ArH), 6.73e6.75
(m, 2H, ArH), 5.16e5.20 (m, 1H, CH), 4.11 (d, J¼5.8 Hz, 1H, CH),
3.96e4.00 (m, 1H, NCH2), 3.71 (s, 3H, OCH3), 3.57e3.65 (m, 3H,
NCH2), 2.05e2.11 (m, 2H, CH2); 13C NMR (125 MHz, DMSO-d6):
d
¼189.2, 168.1, 166.7, 158.6, 156.0, 142.4, 134.0, 132.0, 129.6, 128.8,
128.8, 128.0, 127.6, 126.3, 114.2, 90.3, 55.2, 55.2, 40.8, 39.8, 38.6,
21.5; HRMS (TOF ESþ): m/z calcd for C29H28N3O4 [(MþH)þ],
482.2074; found, 482.2079.
4.2.8. N-(9-(4-Methoxybenzoyl)-8-(4-methoxyphenyl)-6-oxo-
2,3,4,6,7,8-hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzam-ide
5h. White solid; mp 115e117 ꢀC; IR (KBr): 3788, 3414, 1608, 1512,
1247, 1025, 837, 739 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d¼12.79
(br, 1H, NH), 7.75 (d, J¼7.7 Hz, 2H, ArH), 7.69 (br, 1H, NH), 7.50e7.56
(m, 1H, ArH), 7.40e7.47 (m, 2H, ArH), 6.99e7.03 (m, 2H, ArH),
6.76e6.85 (m, 6H, ArH), 5.16e5.18 (m, 1H, CH), 4.22 (d, J¼6.1 Hz, 1H,
CH), 3.95e4.03 (m, 1H, NCH2), 3.72 (s, 6H, OCH3), 3.56e3.72 (m, 3H,
NCH2), 2.04e2.08 (m, 2H, CH2); 13C NMR (125 MHz, DMSO-d6):
d
¼189.2, 168.6, 167.2, 160.3, 159.1, 156.4, 135.4, 134.5, 132.5, 132.3,
130.2, 129.3, 128.7, 128.2, 114.8, 113.8, 90.8, 55.9, 55.8, 41.4, 39.8,
39.0, 21.1; HRMS (TOF ESþ): m/z calcd for C30H30N3O5 [(MþH)þ],
512.2180; found, 512.2188.
4.2.9. N-(9-(4-Fluorobenzoyl)-6-oxo-8-(thiophen-2-yl)-2,3,4,6,7,8-
hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzamide
solid; mp 109e110 ꢀC; IR (KBr): 3714, 3425, 1699, 1608, 1489, 1238,
1158, 713 cmꢁ1 1H NMR (500 MHz, CDCl3):
¼12.73 (br, 1H, NH),
7.78 (d, J¼7.4 Hz, 2H, ArH), 7.51e7.53 (m, 1H, ArH), 7.42e7.47 (m,
5i. White
;
d
Scheme 3. Plausible mechanism for the formation of 5e7.

X. Chen et al. / Tetrahedron 69 (2013) 9224e9236
9233
2H, ArH), 7.21e7.27 (m, 2H, ArH), 7.29e7.21 (m, 1H, ArH), 6.95e6.98
(m, 2H, ArH), 6.92e6.94 (m, 1H, ArH), 6.86 (d, J¼4.9 Hz, 2H, ArH),
6.65 (br, 1H, NH), 5.17e5.20 (m, 1H, CH), 4.67 (d, J¼5.2 Hz, 1H, CH),
4.08e4.14 (m, 1H, NCH2), 3.52e3.70 (m, 3H, NCH2), 2.13e2.19 (m,
55.4, 40.2, 39.0, 38.5, 21.4; HRMS (TOF ESþ): m/z calcd for
C
27H26N3O4S [(MþH)þ], 488.1639; found, 488.1645.
4.2.14. N-(9-(4-Fluorobenzoyl)-8-(furan-2-yl)-6-oxo-2,3,4,6,7,8-
hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzamide 5n. White
solid; mp 212e214 ꢀC; IR (KBr): 3792, 3417, 1706, 1610, 1529, 1235,
1013, 841 cmꢁ1 1H NMR (500 MHz, CDCl3):
2H, CH2); 13C NMR (125 MHz, CDCl3):
d
¼190.5,168.3,167.5,162.7 (d,
J¼245.0 Hz), 155.6, 143.4, 137.9, 134.1, 132.4, 129.1, 128.9, 127.5,
127.5, 126.2, 125.6, 115.5 (d, J¼21.3 Hz), 115.4 (d, J¼21.3 Hz), 92.0,
55.4, 40.2, 39.1, 38.4, 21.3; HRMS (TOF ESþ): m/z calcd for
;
d¼12.74 (br, 1H, NH),
7.72 (d, J¼7.5 Hz, 2H, ArH), 7.49e7.51 (m, 1H, ArH), 7.40e7.44 (m,
2H, ArH), 7.26e7.32 (m, 3H, ArH), 7.01e7.04 (m, 2H, ArH), 6.85 (br,
1H, NH), 6.24e6.28 (m, 1H, ArH), 5.85e5.89 (m, 1H, ArH), 5.16e5.19
(m, 1H, CH), 4.48 (d, J¼5.6 Hz, 1H, CH), 4.14e4.18 (m, 1H, NCH2),
3.52e3.68 (m, 3H, NCH2), 2.11e2.14 (m, 2H, CH2); 13C NMR
C
26H23FN3O3S [(MþH)þ], 476.1439; found, 476.1433.
4.2.10. N-(9-(4-Chlorobenzoyl)-6-oxo-8-(thiophen-2-yl)-2,3,4,6,7,8-
hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzamide 5j. White
solid; mp 207e209 ꢀC; IR (KBr): 3730, 3406, 1704, 1613, 1530, 1242,
903, 724 cmꢁ1 1H NMR (500 MHz, CDCl3):
(125 MHz, CDCl3):
d
¼190.2, 168.6, 167.7, 163.4 (d, J¼246.0 Hz), 156.1,
;
d¼12.72 (br, 1H, NH),
153.9, 142.9, 138.0, 134.3, 132.2, 129.0, 128.9, 127.5, 115.6 (d,
J¼26.6 Hz), 115.4 (d, J¼26.6 Hz), 107.8, 108.3, 88.9, 54.5, 40.0, 39.1,
37.0, 21.2; HRMS (TOF ESþ): m/z calcd for C26H23FN3O4 [(MþH)þ],
460.1667; found, 460.1672.
7.78 (d, J¼7.1 Hz, 2H, ArH), 7.51e7.55 (m, 1H, AreH), 7.43e7.47 (m,
2H, ArH), 7.25e7.29 (m, 3H, ArH), 7.17e7.21 (m, 3H, ArH), 6.92e6.94
(m, 1H, ArH), 6.84e6.86 (m, 1H, ArH), 6.65 (br, 1H, NH), 5.17e5.19
(m, 1H, CH), 4.64 (d, J¼5.2 Hz, 1H, CH), 4.09e4.13 (m, 1H, NCH2),
3.52e3.74 (m, 3H, NCH2), 2.14e2.20 (m, 2H, CH2); 13C NMR
4.2.15. N-(9-(4-Chlorobenzoyl)-8-(furan-2-yl)-6-oxo-2,3,4,6,7,8-
hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl) benzamide 5o. White
solid; mp 179e180 ꢀC; IR (KBr): 3783, 3223, 1707, 1653, 1610, 1237,
(125 MHz, CDCl3):
d
¼190.3, 168.3, 167.6, 155.7, 143.4, 140.1, 135.4,
134.1, 132.4, 129.1, 128.7, 128.3, 127.5, 127.5, 126.2, 125.6, 92.0, 55.4,
40.2, 39.1, 38.3, 21.3; HRMS (TOF ESþ): m/z calcd for C26H23ClN3O3S
[(MþH)þ], 492.1143; found, 492.1141.
923, 698 cmꢁ1
;
1H NMR (500 MHz, CDCl3):
d
¼12.73 (br, 1H, NH),
7.72 (d, J¼7.6 Hz, 2H, ArH), 7.49e7.53 (m, 1H, ArH), 7.40e7.44 (m,
2H, ArH), 7.28e7.33 (m, 3H, ArH), 7.31 (t, J¼9.3 Hz, 2H, ArH), 6.84
(br, 1H, NH), 6.25e6.27 (m, 1H, ArH), 5.87 (d, J¼2.7 Hz, 1H, ArH),
5.16e5.19 (m, 1H, CH), 4.45 (d, J¼5.8 Hz, 1H, CH), 4.13e4.19 (m, 1H,
NCH2), 3.53e3.70 (m, 3H, NCH2), 2.10e2.16 (m, 2H, CH2); 13C NMR
4.2.11. N-(9-Benzoyl-6-oxo-8-(thiophen-2-yl)-2,3,4,6,7,8-hexa-hy-
dro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzamide 5k. White solid; mp
169e171 ꢀC; IR (KBr): 3788, 3435, 1616, 1529, 1240, 1164, 706,
531 cmꢁ1
;
1H NMR (500 MHz, CDCl3):
d
¼12.64 (br, 1H, NH), 7.67
(125 MHz, CDCl3):
d
¼189.9, 168.6, 167.7, 156.1, 153.8, 143.0, 140.2,
(d, J¼7.5 Hz, 2H, ArH), 7.41e7.45 (m, 1H, ArH), 7.32e7.36 (m, 2H,
ArH), 7.18e7.24 (m, 3H, ArH), 7.14 (d, J¼6.7 Hz, 2H, ArH), 7.10 (d,
J¼4.7 Hz, 1H, ArH), 6.82e6.84 (m, 1H, ArH), 6.72 (d, J¼5.9 Hz, 1H,
ArH), 6.53 (br, 1H, NH), 5.10e5.14 (m, 1H, CH), 4.56 (d, J¼5.6 Hz,
1H, CH), 3.99e4.05 (m, 1H, NCH2), 3.45e3.60 (m, 3H, NCH2),
135.2, 134.3, 132.3, 129.0, 128.8, 128.3, 127.5, 110.8, 108.4, 88.9, 54.4,
40.0, 39.1, 37.0, 21.2; HRMS (TOF ESþ): m/z calcd for C26H23ClN3O4
[(MþH)þ], 476.1372; found, 476.1371.
4.2.16. N-(9-Benzoyl-8-(furan-2-yl)-6-oxo-2,3,4,6,7,8-hexahy-dro-
1H-pyrido[1,2-a]pyrimidin-7-yl) benzamide 5p. White solid; mp
187e189 ꢀC; IR (KBr): 3714, 3426, 1706, 1614, 1524, 1374, 1157,
2.04e2.10 (m, 2H, CH2); 13C NMR (125 MHz, CDCl3):
d¼191.8,
168.4, 167.5, 155.5, 143.6, 141.7, 134.2, 132.3, 129.4, 129.0, 128.4,
127.5, 127.5, 126.7, 126.2, 125.4, 92.0, 55.3, 40.2, 39.1, 38.4, 21.4;
HRMS (TOF ESþ): m/z calcd for C26H24N3O3S [(MþH)þ], 458.1533;
found, 458.1539.
918 cmꢁ1
;
1H NMR (500 MHz, CDCl3):
d
¼12.76 (br, 1H, NH),
7.98e8.05 (m, 2H, ArH), 7.69e7.73 (m, 1H, ArH), 7.43e7.53 (m, 2H,
ArH), 7.30e7.36 (m, 3H, ArH), 7.27e7.31 (m, 3H, ArH), 6.83 (br, 1H,
NH), 6.23e6.27 (m, 1H, ArH), 5.83e5.87 (m, 1H, ArH), 5.18e5.22 (m,
1H, CH), 4.44e4.48 (m, 1H, CH), 4.11e4.17 (m, 1H, NCH2), 3.50e3.67
(m, 3H, NCH2), 2.06e2.14 (m, 2H, CH2); 13C NMR (125 MHz, CDCl3):
4.2.12. N-(9-(4-Methylbenzoyl)-6-oxo-8-(thiophen-2-yl)-2,3,4,6,7,8-
hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl) benzamide 5l. White
solid; mp 222e223 ꢀC; IR (KBr): 3832, 3418, 1703, 1659, 1612, 1243,
d
¼191.4, 168.6, 167.7, 156.0, 154.1, 142.9, 141.9, 134.4, 132.2, 129.3,
918, 706 cmꢁ1
;
1H NMR (500 MHz, CDCl3):
d
¼12.77 (br, 1H, NH),
129.0, 128.6, 127.5, 126.7, 110.8, 108.3, 88.9, 54.4, 40.0, 39.0, 37.0,
21.2; HRMS (TOF ESþ): m/z calcd for C26H24N3O4 [(MþH)þ],
442.1761; found, 442.1763.
7.78 (d, J¼7.8 Hz, 2H, ArH), 7.50e7.54 (m, 1H, ArH), 7.42e7.46 (m,
2H, ArH), 7.20 (d, J¼5.0 Hz, 1H, ArH), 7.15e7.17 (m, 2H, ArH),
7.06e7.10 (m, 2H, ArH), 6.92e6.94 (m, 1H, ArH), 6.84 (d, J¼5.9 Hz,
1H, ArH), 6.66 (br, 1H, NH), 5.19e5.22 (m, 1H, CH), 4.70 (d, J¼5.6 Hz,
1H, CH), 4.08e4.14 (m, 1H, NCH2), 3.50e3.70 (m, 3H, NCH2), 2.33 (s,
3H, CH3), 2.13e2.17 (m, 2H, CH2); 13C NMR (125 MHz, CDCl3):
4.2.17. N-(8-(Furan-2-yl)-9-(4-methylbenzoyl)-6-oxo-2,3,4,6,7,8-
hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl) benzamide 5q. White
solid; mp 237e239 ꢀC; IR (KBr): 3783, 3425, 1705, 1611, 1523, 1238,
d
¼192.0, 168.4, 167.5, 155.4, 143.7, 139.3, 138.9, 134.2, 132.3, 129.1,
821, 702 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d
¼12.57 (br, 1H, NH),
129.1, 127.5, 127.5, 126.8, 126.1, 125.4, 92.0, 55.4, 40.2, 39.0, 38.5,
21.7, 21.4; HRMS (TOF ESþ): m/z calcd for C27H26N3O3S [(MþH)þ],
472.1689; found, 472.1699.
7.99 (br,1H, NH), 7.78 (d, J¼6.9 Hz, 2H, ArH), 7.53e7.55 (m,1H, ArH),
7.46e7.50 (m, 1H, ArH), 7.44e7.47 (m, 2H, ArH), 7.12e7.15 (m, 2H,
ArH), 7.05e7.08 (m, 2H, ArH), 6.31e6.35 (m, 1H, ArH), 5.95e5.99
(m, 1H, ArH), 5.17e5.21 (m, 1H, CH), 4.30e4.37 (m, 1H, CH),
3.95e4.05 (m, 1H, NCH2), 3.52e3.62 (m, 3H, NCH2), 2.29 (s, 3H,
CH3), 1.99e2.05 (m, 2H, CH2); 13C NMR (125 MHz, DMSO-d6):
4.2.13. N-(9-(4-Methoxybenzoyl)-6-oxo-8-(thiophen-2-yl)-
2,3,4,6,7,8-hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)
5m. White solid; mp 116e119 ꢀC; IR (KBr): 3832, 3415, 1674, 1607,
1378,1243,1169, 709 cmꢁ1; 1H NMR (500 MHz, CDCl3):
benzamide
d
¼188.8, 168.1, 166.8, 155.8, 154.4, 143.0, 139.6, 138.4, 134.1, 131.9,
d¼12.68 (br,
128.8, 128.7, 128.7, 127.8, 126.5, 110.7, 107.4, 88.4, 54.5, 39.7, 38.5,
36.7, 21.2, 20.5; HRMS (TOF ESþ): m/z calcd for C27H26N3O4
[(MþH)þ], 456.1918; found, 456.1915.
1H, NH), 7.69 (d, J¼7.5 Hz, 2H, ArH), 7.41e7.45 (m, 1H, ArH),
7.32e7.36 (m, 2H, ArH), 7.15 (d, J¼8.4 Hz, 2H, ArH), 7.09 (d, J¼4.8 Hz,
1H, ArH), 6.82e6.84 (m, 1H, ArH), 6.77e6.79 (m, 1H, ArH), 6.71 (d,
J¼8.4 Hz, 2H, ArH), 6.59 (br, 1H, NH), 5.08e5.11 (m, 1H, CH), 4.67 (d,
J¼5.4 Hz, 1H, CH), 3.97e4.01 (m, 1H, NCH2), 3.69 (s, 3H, OCH3),
3.40e3.58 (m, 3H, NCH2), 2.00e2.06 (m, 2H, CH2); 13C NMR
4.2.18. N-(8-(Furan-2-yl)-9-(4-methoxybenzoyl)-6-oxo-2,3,4,6,7,8-
hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzamide
solid; mp 231e232 ꢀC; IR (KBr): 3788, 3217, 1705, 1649, 1607, 1164,
927, 768 cmꢁ1 1H NMR (500 MHz, CDCl3):
¼12.77 (br, 1H, NH),
7.72 (d, J¼7.3 Hz, 2H, ArH), 7.47e7.51 (m, 1H, ArH), 7.38e7.42 (m,
5r. White
(125 MHz, CDCl3):
134.3, 132.3, 129.1, 128.7, 127.5, 127.5, 126.2, 125.5, 113.7, 92.0, 55.6,
d
¼191.3, 168.4, 167.5, 160.7, 155.4, 143.8, 134.4,
;
d

9234
X. Chen et al. / Tetrahedron 69 (2013) 9224e9236
2H, ArH), 7.24e7.27 (m, 2H, ArH), 6.82e6.85 (m, 2H, ArH), 6.25 (t,
J¼2.4 Hz, 1H, ArH), 5.89 (d, J¼3.0 Hz, 1H, ArH), 5.16e5.20 (m, 1H,
CH), 4.56 (d, J¼5.8 Hz, 1H, CH), 4.11e4.18 (m, 1H, NCH2), 3.79 (s, 3H,
OCH3), 3.48e3.65 (m, 3H, NCH2), 2.04e2.10 (m, 2H, CH2); 13C NMR
20.5; HRMS (TOF ESþ): m/z calcd for C32H28FN4O4 [(MþH)þ],
551.2089; found, 551.2091.
4.2.23. N-(8-(1-Acetyl-1H-indol-3-yl)-9-(4-chlorobenzoyl)-6-oxo-
2,3,4,6,7,8-hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)-benzamide
5w. White solid; mp 269e271 ꢀC; IR (KBr): 3824, 3426, 1670, 1615,
(125 MHz, CDCl3):
d
¼191.2, 168.2, 167.3, 155.4, 153.8, 142.4, 134.0,
131.7, 128.5, 128.5, 128.1, 127.0, 113.3, 110.3, 107.8, 88.5, 55.1, 54.0,
39.5, 38.5, 36.7, 20.8; HRMS (TOF ESþ): m/z calcd for C27H26N3O5
[(MþH)þ], 472.1867; found, 472.1877.
1531,1379,1005, 752 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d
¼12.81 (br,
1H, NH), 8.33 (br, 1H, NH), 7.40e7.49 (m, 3H, ArH), 7.27e7.34 (m,
3H, ArH), 7.07e7.16 (m, 6H, ArH), 6.98e7.03 (m, 1H, ArH), 6.62 (d,
J¼6.1 Hz,1H, ArH), 5.29e5.32 (m,1H, CH), 4.73 (d, J¼5.8 Hz,1H, CH),
4.20e4.28 (m, 1H, NCH2), 3.59e3.72 (m, 3H, NCH2), 2.56 (s, 3H,
4.2.19. N-(9-(4-Chlorobenzoyl)-8-(5-methylfuran-2-yl)-6-oxo-
2,3,4,6,7,8-hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl) benz-amide
5s. White solid; mp 203e204 ꢀC; IR (KBr): 3729, 3337, 1712,
CH3), 1.95e2.22 (m, 2H, CH2); 13C NMR (125 MHz, CDCl3):
d
¼189.9,
1622, 1245, 1164, 788, 706 cmꢁ1
;
1H NMR (500 MHz, DMSO-d6):
168.6, 168.4, 168.0, 155.6, 139.9, 135.5, 133.9, 132.2, 130.3, 128.8,
128.7, 128.3, 127.5, 126.1, 124.2, 123.2, 122.4, 119.8, 116.6, 91.2, 56.0,
40.1, 39.1, 34.1, 24.5, 21.5; HRMS (TOF ESþ): m/z calcd for
d
¼12.48 (br, 1H, NH), 8.07 (br, 1H, NH), 7.77e7.85 (m, 2H, ArH),
7.51e7.55 (m, 1H, ArH), 7.40e7.48 (m, 2H, ArH), 7.37e7.45 (m, 2H,
ArH), 5.91e5.95 (m, 1H, ArH), 5.85e5.91 (m, 1H, ArH), 5.15e5.21
(m, 1H, CH), 4.12e4.15 (m, 1H, CH), 3.93e4.01 (m, 1H, NCH2),
3.50e3.61 (m, 3H, NCH2), 2.13 (s, 3H, CH3), 1.99e2.05 (m, 2H, CH2);
C
32H28ClN4O4 [(MþH)þ], 567.1794; found, 567.1791.
4.2.24. N-(8-(1-Acetyl-1H-indol-3-yl)-9-benzoyl-6-oxo-2,3,4,6,7,8-
hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzamide 5x. White
solid; mp 277e279 ꢀC; IR (KBr): 3828, 3416, 1702, 1619, 1380, 1244,
702, 539 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
13C NMR (125 MHz, DMSO-d6):
d
¼187.1, 168.0, 166.8, 156.0, 152.3,
151.6, 141.0, 134.1, 133.5, 131.9, 128.7, 128.7, 128.4, 128.4, 127.8,
108.2, 106.7, 88.4, 54.5, 39.4, 38.6, 36.6, 20.4, 13.6; HRMS (TOF
ESþ): m/z calcd for C27H25ClN3O4 [(MþH)þ], 490.1528; found,
490.1538.
d
¼12.67 (br,1H, NH),
8.26 (br, 1H, NH), 7.92 (d, J¼6.9 Hz,1H, ArH), 7.51e7.54 (m, 2H, ArH),
7.41e7.47 (m, 1H, ArH), 7.24e7.39 (m, 5H, ArH), 7.10e7.23 (m, 4H,
ArH), 6.85e6.91 (m, 1H, ArH), 6.74e6.81 (m, 1H, ArH), 5.28e5.32
(m, 1H, CH), 4.53 (d, J¼6.0 Hz, 1H, CH), 4.18e4.22 (m, 1H, NCH2),
3.43e3.54 (m, 3H, NCH2), 2.61 (s, 3H, CH3), 2.08e2.16 (m, 2H, CH2);
4.2.20. N-(9-Benzoyl-8-(5-methylfuran-2-yl)-6-oxo-2,3,4,6,7,8-
hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl) benzamide 5t. White
solid; mp 205e207 ꢀC; IR (KBr): 3787, 3402, 1702, 1653, 1613,
13C NMR (100 MHz, DMSO-d6):
d
¼188.5, 169.8, 168.3, 167.3, 156.0,
1245, 1171, 802 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d
¼12.77 (br, 1H,
142.3, 135.4, 134.2, 131.8, 130.8, 128.9, 128.5, 128.2, 127.9, 126.5,
125.3, 124.3, 123.3, 121.9, 119.0, 116.2, 90.6, 55.8, 39.4, 38.7, 33.6,
22.4, 20.6; HRMS (TOF ESþ): m/z calcd for C32H29N4O4 [(MþH)þ],
533.2183; found, 533.2184.
NH), 7.74 (d, J¼7.5 Hz, 2H, ArH), 7.47e7.52 (m, 1H, ArH),
7.39e7.44 (m, 2H, ArH), 7.31e7.35 (m, 3H, ArH), 7.27e7.31 (m, 2H,
ArH), 6.86 (br, 1H, NH), 5.82e5.86 (m, 1H, ArH), 5.80 (d, J¼6.9 Hz,
1H, ArH), 5.18e5.22 (m, 1H, CH), 4.34 (d, J¼5.6 Hz, 1H, CH),
4.12e4.19 (m, 1H, NCH2), 3.53e3.65 (m, 3H, NCH2), 2.56 (s, 3H,
CH3), 2.11e2.14 (m, 2H, CH2); 13C NMR (125 MHz, CDCl3):
4.2.25. N-(8-(1-Acetyl-1H-indol-3-yl)-9-(4-methylbenzoyl)-6-oxo-
2,3,4,6,7,8-hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)-benzamide
5y. White solid; mp 263e266 ꢀC; IR (KBr): 3726, 3418, 1703, 1614,
d
¼191.3, 168.7, 167.6, 156.1, 152.4, 152.2, 141.9, 134.5, 132.1, 129.3,
129.0, 128.5, 127.5, 126.7, 109.2, 106.7, 89.1, 54.4, 40.0, 39.0, 37.1,
21.3, 14.0; HRMS (TOF ESþ): m/z calcd for C27H26N3O4 [(MþH)þ],
456.1918; found, 456.1923.
1378, 1169, 927, 747 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d
¼12.85 (br,
1H, NH), 8.33 (br, 1H, NH), 7.42e7.45 (m, 3H, ArH), 7.26e7.31 (m,
3H, ArH), 7.08e7.12 (m, 4H, ArH), 6.97e7.00 (m, 1H, ArH), 6.93 (d,
J¼7.0 Hz, 2H, ArH), 6.56e6.59 (m, 1H, ArH), 5.31e5.34 (m, 1H, CH),
4.78 (d, J¼5.0 Hz, 1H, CH), 4.20e4.24 (m, 1H, NCH2), 3.54e3.62 (m,
3H, NCH2), 2.25 (s, 3H, CH3), 2.13e2.21 (m, 2H, CH2), 1.77 (s, 3H,
4.2.21. N-(9-(4-Methoxybenzoyl)-8-(5-methylfuran-2-yl)-6-oxo-
2,3,4,6,7,8-hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)benz-amide
5u. White solid; mp 189e192 ꢀC; IR (KBr): 3440, 3363, 1691, 1644,
CH3); 13C NMR (125 MHz, CDCl3):
d
¼191.7, 168.8, 168.5, 168.0, 155.3,
1524, 1245, 787, 608 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
¼12.70 (br,
139.5,138.7,136.1,134.0,132.1,130.5,129.1,128.8,127.5,126.8,125.9,
124.0, 123.2, 122.7, 120.0, 116.6, 91.3, 56.0, 40.1, 39.1, 34.2, 24.4, 21.6;
HRMS (TOF ESþ): m/z calcd for C33H31N4O4 [(MþH)þ], 547.2340;
found, 547.2340.
1H, NH), 7.67 (d, J¼7.3 Hz, 2H, ArH), 7.39e7.44 (m, 1H, ArH),
7.31e7.36 (m, 2H, ArH), 7.19e7.24 (m, 3H, ArH), 6.80 (br, 1H, NH),
5.75 (d, J¼1.8 Hz, 2H, ArH), 5.10 (t, J¼6.4 Hz, 1H, CH), 4.35 (d,
J¼5.6 Hz, 1H, CH), 4.03e4.09 (m, 1H, NCH2), 3.72 (s, 3H, OCH3),
3.40e3.55 (m, 3H, NCH2), 2.12 (s, 3H, CH3), 1.98e2.06 (m, 2H, CH2);
4.2.26. N-(8-(1-Acetyl-1H-indol-3-yl)-9-(4-methoxybenzoyl)-6-oxo-
13C NMR (100 MHz, CDCl3):
d
¼189.5, 167.3, 166.2, 159.1, 154.5, 151.0,
2,3,4,6,7,8-hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)
5z. White solid; mp 256e258 ꢀC; IR (KBr): 3714, 3305, 1712, 1696,
1602, 1250, 924, 751 cmꢁ1; 1H NMR (500 MHz, CDCl3):
benzamide
150.9, 133.1, 130.7, 127.5, 127.5, 127.2, 126.1, 112.4, 107.8, 105.3, 87.7,
54.2, 53.1, 38.5, 37.6, 35.8, 19.9, 12.6; HRMS (TOF ESþ): m/z calcd for
d
¼12.78 (br,
C
28H28N3O5[(MþH)þ], 486.2023; found, 486.2033.
1H, NH), 8.29 (br,1H, NH), 7.37e7.42 (m, 3H, ArH), 7.21e7.27 (m, 3H,
ArH), 7.14 (d, J¼6.1 Hz, 2H, ArH), 7.07e7.10 (m, 2H, ArH), 6.93e6.96
(m, 1H, ArH), 6.58e6.63 (m, 3H, ArH), 5.24e5.28 (m, 1H, CH), 4.77
(d, J¼5.0 Hz, 1H, CH), 4.16e4.22 (m, 1H, NCH2), 3.68 (s, 3H, OCH3),
3.53e3.61 (m, 3H, NCH2), 2.38 (s, 3H, CH3), 2.07e2.17 (m, 2H, CH2);
4.2.22. N-(8-(1-Acetyl-1H-indol-3-yl)-9-(4-fluorobenzoyl)-6-oxo-
2,3,4,6,7,8-hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)-benzamide
5v. White solid; mp 265e268 ꢀC; IR (KBr): 3796, 3400, 1703, 1612,
1378, 1273, 845, 749 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d
¼12.63
13C NMR (125 MHz, CDCl3):
d
¼190.8,168.7,168.0,160.7,155.3,136.0,
(br, 1H, NH), 8.27 (br, 1H, NH), 7.92e8.00 (m, 1H, ArH), 7.52e7.60
(m, 2H, ArCH), 7.40e7.46 (m, 1H, ArCH), 7.29e7.38 (m, 3H, ArCH),
7.13e7.23 (m, 3H, ArCH), 6.92e7.02 (m, 3H, ArCH), 6.80e6.86 (m,
1H, ArCH), 5.29e5.33 (m,1H, CH), 4.49e4.52 (m,1H, CH), 4.02e4.08
(m, 1H, NCH), 3.59e3.76 (m, 2H, NCH2), 2.60 (s, 3H, CH3), 2.08e2.16
134.1, 134.0, 132.1, 130.4, 128.8, 128.6, 127.5, 125.9, 124.0, 123.3,
122.6,119.9,116.6,113.7, 91.2, 56.0, 55.6, 40.3, 34.3, 24.4, 21.5; HRMS
(TOF ESþ): m/z calcd for C33H31N4O5 [(MþH)þ], 563.2289; found,
563.2284.
(m, 2H, CH2); 13C NMR (125 MHz, DMSO-d6):
d
¼187.2, 169.7, 168.2,
4.2.27. N-(9-Benzoyl-6-oxo-8-phenyl-2,3,4,6,7,8-hexahydro-1H-pyr-
ido[1,2-a]pyrimidin-7-yl)-4-fluorobenzamide 5a0. White solid; mp
220e221 ꢀC; IR (KBr): 3411, 3064, 1613, 1381, 1241, 1163, 703,
167.3, 162.3 (d, J¼243.7 Hz), 155.9, 138.7, 135.3, 134.1, 131.7, 130.6,
128.8, 128.4, 128.4, 127.8, 125.0, 124.4,123.2, 121.6, 118.8, 116.2, 115.1
(d, J¼21.3 Hz), 114.9 (d, J¼21.3 Hz), 90.5, 55.7, 39.7, 38.7, 33.6, 24.2,
505 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d¼12.81 (br, 1H, NH),

X. Chen et al. / Tetrahedron 69 (2013) 9224e9236
9235
7.61e7.65 (m, 2H, ArH), 7.15e7.26 (m, 6H, ArH), 7.00e7.06 (m, 4H,
ArH), 6.81e6.83 (m, 2H, ArH), 6.41 (br,1H, NH), 5.21 (t, J¼6.6 Hz,1H,
CH), 4.29 (d, J¼6.6 Hz, 1H, CH), 4.09e4.15 (m, 1H, NCH2), 3.74 (s, 3H,
OCH3), 3.51e3.71 (m, 3H, NCH2), 2.12e2.17 (m, 2H, CH2); 13C NMR
37.7; HRMS (TOF ESþ): m/z calcd for C25H21FN3O4 [(MþH)þ],
446.1511; found, 446.1504.
4.2.32. N-(8-Benzoyl-7-(furan-2-yl)-5-oxo-1,2,3,5,6,7-hexahy-droi-
midazo[1,2-a]pyridin-6-yl) benzamide 6b0. White solid; mp
105e108 ꢀC; IR (KBr): 3788, 3423, 1699, 1636, 1522, 1273, 1017,
(100 MHz, CDCl3):
d
¼192.0,168.1,164.9 (d, J¼251.0 Hz),166.0,155.4,
141.5, 139.2, 130.0, 129.4, 129.3, 128.7, 128.7, 128.3, 127.9, 127.5,
126.1, 115.8 (d, J¼22.0 Hz), 115.5 (d, J¼22.0 Hz), 90.3, 54.8, 41.8, 39.7,
38.7, 20.9; HRMS (TOF ESþ): m/z calcd for C28H25FN3O3 [(MþH)þ],
470.1847; found, 470.1850.
708 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d
¼9.66 (br, 1H, NH), 7.69 (d,
J¼7.7 Hz, 2H, ArH), 7.49e7.53 (m, 1H, ArH), 7.39e7.43 (m, 2H, ArH),
7.28e7.39 (m, 6H, ArH), 6.73 (br, 1H, NH), 6.23e6.25 (m, 1H, ArH),
5.79e5.81 (m, 1H, ArH), 5.22e5.26 (m, 1H, CH), 4.66 (d, J¼6.0 Hz,
1H, CH), 4.15e4.19 (m, 1H, NCH2), 3.92e4.05 (m, 3H, NCH2); 13C
4.2.28. 4-Fluoro-N-(9-(4-methoxybenzoyl)-6-oxo-8-phenyl-
2,3,4,6,7,8-hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)benzamide
5b0. White solid; mp>300 ꢀC; IR (KBr): 3415, 3232, 1704, 1528,
NMR (125 MHz, CDCl3):
d
¼192.3, 167.4, 166.7, 156.1, 153.5, 142.3,
140.6, 133.8, 131.7, 129.4, 128.5, 128.1, 127.0, 126.4, 110.3, 107.8, 86.9,
54.3, 43.0, 42.3, 37.2; HRMS (TOF ESþ): m/z calcd for C25H22N3O4
[(MþH)þ], 428.1605; found, 428.1601.
1238, 1029, 844, 567 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
¼12.86
(br, 1H, NH), 7.63e7.67 (m, 2H, ArH), 7.23e7.26 (m, 3H, ArH),
7.02e7.08 (m, 4H, ArH), 6.88e6.91 (m, 2H, ArH), 6.70 (d, J¼8.6 Hz,
2H, ArH), 6.47 (br, 1H, NH), 5.20 (t, J¼6.5 Hz, 1H, CH), 4.39 (d,
J¼6.5 Hz, 1H, CH), 4.09e4.16 (m, 1H, NCH2), 3.74 (s, 3H, OCH3),
3.51e3.69 (m, 3H, NCH2), 2.14e2.18 (m, 2H, CH2); 13C NMR
4.2.33. N-(7(-Acetyl-1H-indole-3-yl)-8-benzoyl-5-oxo-1,2,3,5,6,7-
hexahydroimidazo[1,2-a]pyridine-6-yl) benzamide 6c0. White solid;
mp 213e214 ꢀC; IR (KBr): 3726, 3425, 1699, 1638, 1524, 1258, 1012,
(100 MHz, CDCl3):
d
¼191.5, 168.1, 164.9 (d, J¼251.0 Hz), 166.0,
747 cmꢁ1
;
1H NMR (500 MHz, CDCl3):
d
¼9.68 (br, 1H, NH),
160.1, 155.3, 139.2, 134.2, 130.1, 129.4, 129.3, 128.7, 128.4, 128.1,
127.5, 115.8 (d, J¼22.0 Hz), 115.6 (d, J¼22.0 Hz), 90.4, 55.2, 55.0,
41.8, 39.7, 38.6, 21.0; HRMS (TOF ESþ): m/z calcd for C29H27FN3O4
[(MþH)þ], 500.1980; found, 500.1985.
8.24e8.27 (m, 1H, ArH), 8.10 (d, J¼7.3 Hz,1H, ArH), 7.49 (d, J¼7.6 Hz,
2H, ArH), 7.40e7.44 (m, 1H, ArH), 7.26e7.32 (m, 3H, ArH), 7.16e7.22
(m, 5H, ArH), 6.86e6.89 (m, 1H, ArH), 6.79e6.83 (m, 1H, ArH),
5.30e5.33 (m, 1H, CH), 4.61 (d, J¼6.8 Hz, 1H, CH), 4.03e4.09 (m, 1H,
NCH2), 3.79e3.99 (m, 3H, NCH2), 2.59 (s, 3H, CH3); 13C NMR
4.2.29. N-(9-(4-Fluorobenzoyl)-6-oxo-8-(thiophen-2-yl)-2,3,4,6,7,8-
hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)-4-methylbenz-amide
5c0. White solid; mp 267e269 ꢀC; IR (KBr): 3420, 3252, 1704, 1605,
(125 MHz, CDCl3):
d
¼189.7, 170.0, 167.6, 167.1, 156.1, 141.7, 135.3;
134.1,131.7,130.7,129.4,128.3,128.2,127.8,126.6,124.9,124.1,123.2,
122.2, 118.9, 116.1, 88.4, 55.9, 43.7, 42.4, 34.3, 24.3; HRMS (TOF ESþ):
m/z calcd for C31H27N4O4 [(MþH)þ], 519.2027; found, 519.2028.
1493, 1235, 1142, 842 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
¼7.66 (d,
J¼7.7 Hz, 2H, ArH), 7.16e7.26 (m, 5H, ArH), 6.89e6.97 (m, 3H, ArH),
6.77e6.81 (m, 1H, ArH), 6.62 (br, 1H, NH), 5.16 (t, J¼5.6 Hz, 1H, CH),
4.64 (d, J¼5.4 Hz, 1H, CH), 4.06e4.12 (m, 1H, NCH2), 3.50e3.67 (m,
3H, NCH2), 2.38 (s, 3H, CH3), 2.00e2.08 (m, 2H, CH2), 1.67 (br, 1H,
4.2.34. N-(7(-Acetyl-1H-indole-3-yl)-8-(4-methylbenzoyl)-5-oxo-
1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridine-6-yl) benz-amide
6d0. White solid; mp 270e272 ꢀC; IR (KBr): 3734, 3433, 1702,
NH); 13C NMR (100 MHz, CDCl3):
d
¼190.1, 168.0, 167.1, 163.0 (d,
1640, 1525,1264, 927, 750 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d
¼9.67
J¼247.0 Hz), 155.2, 143.1, 142.5, 137.5, 130.9, 129.3, 128.5, 128.4,
127.1, 127.1, 125.8, 125.1, 115.1 (d, J¼21.0 Hz), 114.9 (d, J¼21.0 Hz),
91.6, 55.0, 39.8, 38.7, 38.0, 21.5, 21.3; HRMS (TOF ESþ): m/z calcd for
(br,1H, NH), 8.33 (br,1H, NH), 7.40e7.43 (m, 3H, ArH), 7.24e7.29 (m,
3H, ArH), 7.12e7.18 (m, 4H, ArH), 6.98e7.01 (m, 1H, ArH), 6.93e6.96
(m, 2H, ArH), 6.56 (d, J¼6.5 Hz, 1H, ArH), 5.32e5.36 (m, 1H, CH),
4.91 (d, J¼6.1 Hz, 1H, CH), 4.19e4.22 (m, 1H, NCH2), 3.90e3.97 (m,
3H, NCH2CH2N), 2.56 (s, 3H, CH3), 2.26 (s, 3H, CH3) 13C NMR
C
27H25FN3O3S [(MþH)þ], 490.1595; found, 490.1592.
4.2.30. N-(9-(4-Methoxybenzoyl)-6-oxo-8-(thiophen-2-yl)-
2,3,4,6,7,8-hexahydro-1H-pyrido[1,2-a]pyrimidin-7-yl)-4-
methylbenz-amide 5d0. White solid; mp>300 ꢀC; IR (KBr): 3418,
(125 MHz, CDCl3):
d
¼192.5, 168.7, 168.2, 167.4, 156.0, 140.3, 138.0;
136.1, 133.9,132.2, 130.4, 129.1, 128.8, 127.5, 127.1, 125.9, 124.1, 123.2,
122.6, 119.9, 116.7, 89.6, 56.5, 43.7, 42.9, 35.0, 24.4, 21.7; HRMS (TOF
ESþ): m/z calcd for C32H29N4O4 [(MþH)þ], 533.2183; found,
533.2188.
2933, 1610, 1374, 1243, 1167, 903, 703 cmꢁ1 1H NMR (400 MHz,
;
CDCl3):
d
¼7.67 (d, J¼8.0 Hz, 2H, ArH), 7.23 (d, J¼8.4 Hz, 4H, ArH),
7.16 (d, J¼5.0 Hz, 1H, ArH), 6.88e6.92 (m, 1H, ArH), 6.76e6.83 (m,
3H, ArH), 6.65 (br, 1H, NH), 5.16 (t, J¼5.9 Hz, 1H, CH), 4.73 (d,
J¼5.6 Hz, 1H, CH), 4.06e4.12 (m, 1H, NCH2), 3.77 (s, 3H, OCH3),
3.49e3.66 (m, 3H, NCH2), 2.39 (s, 3H, CH3), 2.10e2.15 (m, 2H, CH2),
4.2.35. N-(7-(1-Acetyl-1H-indol-3-yl)-8-(4-methoxybenzoyl)-5-oxo-
1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridin-6-yl)benz-amide
6e. White solid; mp 234e237 ꢀC; IR (KBr): 3788, 3427, 1699, 1638,
1.67 (br, 1H, NH); 13C NMR (100 MHz, CDCl3):
d¼191.0, 168.1, 167.0,
1253, 1168, 735, 657 cmꢁ1
;
1H NMR (500 MHz, CDCl3þDMSO-d6):
160.2, 155.0, 143.4, 142.4, 134.0, 131.0, 129.3, 128.2, 127.1, 125.7,
125.0, 113.3, 91.7, 55.2, 55.0, 39.8, 38.6, 38.1, 21.5, 21.0; HRMS (TOF
ESþ): m/z calcd for C28H28N3O4S [(MþH)þ], 502.1795; found,
502.1795.
d
¼9.21 (br, 1H, NH), 7.86 (br, 1H, NH), 6.99 (d, J¼7.6 Hz, 2H, ArH),
6.97e6.81 (m, 1H, ArH), 6.77e6.85 (m, 3H, ArH), 6.71e6.81 (m, 4H,
ArH), 6.62e6.66 (m, 1H, ArH), 6.48e6.52 (m, 1H, ArH), 6.17 (d,
J¼8.6 Hz, 2H, ArH), 4.82e4.86 (m, 1H, CH), 4.35e4.39 (m, 1H, CH),
3.71e3.75 (m, 1H, NCH2), 3.42e3.58 (m, 3H, NCH2), 3.26 (s, 3H,
OCH3), 2.12 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3þDMSO-d6):
4.2.31. N-(8-(4-Fluorobenzoyl)-7-(furan-2-yl)-5-oxo-1,2,3,5,6,7-
hexahydroimidazo[1,2-a]pyridin-6-yl)benzamide 6a. White solid;
mp 226e229 ꢀC; IR (KBr): 3869, 3332, 1699, 1641, 1266, 1154, 1107,
d
¼192.7, 177.6, 169.8, 168.0, 167.0, 161.8, 159.4, 135.1, 133.4, 131.8,
129.9, 128.3, 127.5, 126.0, 125.3, 123.4, 123.3, 120.4, 118.5, 116.2,
114.0, 93.2, 55.5, 55.1, 45.2, 43.1, 34.0, 24.0; HRMS (TOF ESþ): m/z
calcd for C32H29N4O5 [(MþH)þ], 549.2132; found, 549.2139.
847 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d
¼9.66 (br, 1H, NH), 7.68 (d,
J¼7.6 Hz, 2H, ArH), 7.48e7.52 (m, 1H, ArH), 7.38e7.42 (m, 2H, ArH),
7.26e7.35 (m, 3H, ArH), 7.01e7.05 (m, 2H, ArH), 6.73 (br, 1H, ArH),
6.20e6.26 (m, 1H, ArH), 5.81 (d, J¼2.8 Hz, 1H, ArH), 5.17e5.21 (m,
1H, CH), 4.66 (d, J¼6.2 Hz, 1H, CH), 4.14e4.19 (m, 1H, NCH2),
4.2.36. N-(9-(1-Acetyl-1H-indol-3-yl)-10-benzoyl-7-oxo-1,2,3,4,5,7,
8,9-octahydropyrido[1,2-a][1,3]diazepin-8-yl) benzam-ide 7. White
solid; mp 287e289 ꢀC; IR (KBr): 3783, 3417, 1703, 1613, 1381, 1242,
3.90e4.01 (m, 3H, NCH2); 13C NMR (125 MHz, CDCl3):
d¼191.4,
167.9, 167.1, 163.8 (d, J¼249.0 Hz), 156.8, 153.8, 142.9, 137.2, 134.3,
132.3, 129.2 (d, J¼7.5 Hz), 129.2 (d, J¼7.5 Hz), 129.0, 127.5, 115.7 (d,
J¼21.3 Hz), 115.5 (d, J¼21.3 Hz), 110.8, 108.3, 87.3, 54.9, 43.6, 42.8,
1155, 750 cmꢁ1
;
1H NMR (500 MHz, DMSO-d6):
d¼11.77 (br, 1H,
NH), 8.26 (br, 1H, NH), 7.54 (d, J¼7.5 Hz, 3H, ArH), 7.43e7.47 (m, 1H,
ArH), 7.30e7.34 (m, 3H, ArH), 7.20e7.26 (m, 3H, ArH), 7.14e7.20 (m,

9236
X. Chen et al. / Tetrahedron 69 (2013) 9224e9236
Oleksijew, A.; Hutch, T., Sr.; Paige, L.; Flamm, B. Antimicrob. Agents Chemother.
1995, 39, 971e975.
3H, ArH), 6.85e6.89 (m, 1H, ArH), 6.79e6.82 (m, 1H, ArH),
5.30e5.34 (m, 1H, CH), 4.61 (d, J¼5.1 Hz, 1H, CH), 4.49e4.54 (m, 1H,
NCH2), 3.41e3.71 (m, 3H, NCH2), 2.60 (s, 3H, CH3), 1.91e1.98 (m, 2H,
CH2), 1.72e1.80 (m, 2H, CH2); 13C NMR (125 MHz, DMSO-d6):
10. Yin, L.; Hu, Q.-Z.; Hartmann, L. W. J. Med. Chem. 2013, 56, 460e470.
11. (a) Kawasuji, T.; Johns, B. A.; Yoshida, H.; Weatherhead, J. G.; Akiyama, T.; Taishi,
T.; Taoda, Y.; Mikamiyama-Iwata, M.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto,
N.; Yonshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Fujiwara, T. J. Med. Chem.
2013, 56, 1124e1135; (b) Muraglia, E.; Kinzel, O.; Gardelli, C.; Crescenzi, B.;
Donghi, M.; Ferrara, M.; Nizi, E.; Orvieto, F.; Pescatore, G.; Laufer, R.; Gonzalez-
Paz, O.; Marco, A. D.; Fiore, F.; Monteagudo, E.; Fonsi, M.; Felock, P. J.; Rowley,
M.; Summa, V. J. Med. Chem. 2008, 51, 861e874; (c) Jones, E. D.; Vandegraaff, N.;
Le, G.; Choi, N.; Issa, W.; Macfarlane, K.; Thienthong, N.; Winfield, L. J.; Coates, J.
A. V.; Lu, L.; Li, X.-M.; Feng, B.; Yu, C.-J.; Rhodes, D. I.; Deadman, J. J. Bioorg. Med.
Chem. Lett. 2010, 20, 5913e5917.
d
¼190.4, 169.7, 169.2, 167.1, 161.4, 141.9, 134.0, 131.8, 130.5, 129.5,
128.5, 128.2, 127.7, 126.5, 125.2, 124.3, 123.2, 120.7, 119.0, 116.2, 95.4,
56.3, 45.6, 34.0, 26.2, 24.3; HRMS (TOF ESþ): m/z calcd for
C
33H31N4O4 [(MþH)þ], 547.2340; found, 547.2341.
Acknowledgements
12. (a) Wasilke, J. C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105,
€
1001e1020; (b) Tietze, L. F.; Evers, H.; Toppken, E. Angew. Chem., Int. Ed. 2001,
We gratefully acknowledge the financial support of Natural
Science Foundation of China (Nos. 81160384, 21162037, 21262042,
U1202221 and 21362042) and Natural Science Foundation of De-
partment of Education of Yunnan Province (Nos. 2011Z042,
2012HB001, and 2010120303).
40, 903e905.
13. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115e136; (b) Eschenbrenner-Lux, V.;
€
Duckert, H.; Khedkar, V.; Bruss, H.; Waldmann, H.; Kumar, K. Chem.dEur. J.
2013, 19, 2294e2304.
14. (a) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354e366; (b) Pellissier,
H. Tetrahedron 2006, 62, 2143e2173.
15. (a) Lu, L.-Q.; Chen, J.-R.; Xiao, W.-J. Acc. Chem. Res. 2012, 45, 1272e1293; (b)
Ramachary, D. B.; Kishor, M.; Reddy, Y. V. Eur. J. Org. Chem. 2008, 28, 975e993;
(c) Jiang, J.; Guan, X.-Y.; Liu, S.-Y.; Ren, B.-Y.; Ma, X.-C.; Guo, X.; Lv, F.-P.; Wu, X.;
Hu, W.-H. Angew. Chem., Int. Ed. 2013, 52, 1539e1542.
Supplementary data
16. For reviews, see: (a) Huang, Z.-T.; Wang, M.-X. Heterocycles 1994, 37, 1233e1262
For recent studies, see: (b) Yan, S.-J.; Chen, Y.-L.; Liu, L.; He, N.-Q.; Lin, J. Green
Chem. 2010, 12, 2043e2052; (c) Yu, F.-C.; Huang, R.; Ni, H.-C.; Fan, J.; Yan, S.-J.;
Lin, J. Green Chem. 2013, 15, 453e462; (d) Wen, L.-R.; Li, Z.-R.; Li, M.; Cao, H.
Green Chem. 2012, 14, 707e716; (e) Li, M.; Shao, P.; Wang, S.-W.; Kong, W.; Wen,
L.-R. J. Org. Chem. 2012, 77, 8956e8967.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.08.052.
References and notes
17. (a) Yu, F.-C.; Yan, S.-J.; Hu, L.; Wang, Y.-C.; Lin, J. Org. Lett. 2011, 13, 4782e4785;
(b) Yan, S.-J.; Chen, Y.-L.; Liu, L.; Tang, Y.-J.; Lin, J. Tetrahedron Lett. 2011, 52,
465e467; (c) Yan, S.-J.; Huang, C.; Su, C.-X.; Ni, Y.-F.; Lin, J. J. Comb. Chem. 2010,
12, 91e94; (d) Huang, C.; Yan, S.-J.; Zeng, X.-H.; Dai, X.-Y.; Zhang, Y.; Qing, C.;
Lin, J. Eur. J. Med. Chem. 2011, 46, 1172e1180; (e) Wen, L.-R.; Liu, C.; Li, M.; Wang,
L.-J. J. Org. Chem. 2010, 75, 7605e7614; (f) Li, M.; Zhou, Z.-M.; Wen, L.-R.; Qiu, Z.-
X. J. Org. Chem. 2011, 76, 3054e3063; (g) Yang, L.-J.; Yan, S.-J.; Chen, W.; Lin, J.
Synthesis 2010, 20, 3536e3554.
1. (a) Eley, K. L.; Halo, L. M.; Song, Z.-S.; Powles, H.; Cox, R. J.; Bailey, A. M.; Lazarus,
C. M.; Simpson, T. J. ChemBioChem 2007, 8, 289e297; (b) Schmidt, K.; Riese, U.;
Li, Z.-Z.; Hamburger, M. J. Nat. Prod. 2003, 66, 378e383; (c) Schmidt, K.; Gun-
ther, W.; Stoyanova, S.; Schubert, B.; Li, Z.-Z.; Hamburger, M.; Militarione, A. Org.
Lett. 2002, 4, 197e199; (d) Marcaurelle, L. A.; Johannes, C.; Yohannes, D.; Till-
otson, B. P.; Mann, D. Bioorg. Med. Chem. Lett. 2009, 19, 2500e2503.
2. Tabrizi, M. A.; Baraldi, P. G.; Saponaro, G. R.; Moorman, A.; Romagnoli, R.; Preti,
D.; Baraldi, S.; Corciulo, C.; Vincenzi, F.; Borea, P. A.; Varani, K. J. Med. Chem.
2013, 56, 1098e1112.
18. Huang, Z.-T.; Liu, Z.-R. Heterocycles 1986, 24, 2247e2254.
19. Huang, Z.-T.; Tzai, L. H. Chem. Ber. 1986, 2208e2219.
20. Yan, S.-J.; Niu, Y.-F.; Huang, R.; Lin, J. Synlett 2009, 2821e2824.
21. (a) Zhao, M.-X.; Wang, M.-X.; Huang, Z.-T. Tetrahedron 2002, 58, 1309e1316; (b)
Meyer, H. Liebigs Ann. Chem. 1981, 9, 1523e1533; (c) Takahashi, M.; Nozaki, C.;
Shibazaki, Y. Chem. Lett. 1987, 6, 1229e1232; (d) Raymond, C. F. J.; Pravin, P.
Tetrahedron 1998, 54, 6191e6200; (e) Charkrabarti, S.; Panda, K.; Misra, N. C.;
Ila, H.; Junjappa, H. Synlett 2005, 1437e1441; (f) Yu, C. Y.; Yang, P. H.; Zhao, M.
X.; Huang, Z. T. Synlett 2006, 1835e1840; (g) Sukach, V. A.; Bolbut, A. V.; Petin,
A. Y.; Vovk, M. V. Synthesis 2007, 6, 835e844.
22. Jie-Jack, L. Name Reactions in Heterocyclic Chemistry; Wiley: New York, NY
2005; P. 255.
23. (a) Huang, Z.-T.; Wang, M.-X. Synthesis 1992, 12, 1273e1276; (b) Li, Z.-J.;
Charles, D. Synth. Commun. 2001, 31, 527e533; (c) Huang, Z.-T.; Liu, Z.-R. Synth.
Commun. 1989, 19, 943e958.
3. Lucas, S.; Negri, M.; Heim, R.; Zimmer, C.; Hartmann, R. W. J. Med. Chem. 2011,
54, 2307e2319.
4. Aberg, V.; Norman, F.; Chorlle, E.; Westermark, A.; Olofsson, A.; Sauer-Eriksson,
A. E.; Almqvist, F. Org. Biomol. Chem. 2005, 3, 2817e2823.
5. Dragovich, P. S.; Prins, T. J.; Zhou, R.; Johnson, T. O.; Zhou, R.; Johnson, T. O.;
Brown, E. L.; Maldonado, F. C.; Fuhrman, S. A.; Zalman, L. S.; Patick, A. K.;
Matthews, D. A.; Hou, X.-J.; Meador, J. W.; Ferre, R. A.; Worland, S. T. Bioorg.
Med. Chem. Lett. 2002, 12, 733e738.
ꢀ
6. Aberg, V.; Almqvist, F. Org. Biomol. Chem. 2007, 5, 1827e1834.
7. Pemberton, N.; Pinkner, J. S.; Jones, J. M.; Jakobsson, L.; Hultgren, S. J.; Almqvist,
F. Tetrahedron Lett. 2007, 48, 4543e4546.
8. (a) Mynderse, J. S.; Samlaska, S. K.; Fukuda, D. S.; Du Bus, R. H.; Baker, P. J. J.
Antibiot. 1985, 38, 1003e1007; (b) Hunt, A. A.; Mynderse, J. S.; Samlaska, S. K.;
Fukuda, D. S.; Maciak, G. M.; Kirst, H. A.; Occolowitz, J. L.; Swartendruber, J. K.;
Jones, N. D. J. Antibiot. 1988, 41, 771e778.
9. (a) Flamm, R. K.; Vojtko, C.; Chu, D. T. W.; Beyer, Q. L. J.; Hensey, D.; Ramer, N.;
Clement, J. J.; Tanaka, S. K. Antimicrob. Agents Chemother. 1995, 4, 964e970; (b)
Alder, J.; Clement, J.; Meulbroek, J.; Shipkowitz, N.; Mitten, M.; Jarvis, K.;
24. CCDC 953332 (5a) contains all crystallographic details of this publication and is
available free of charge at www.ccdc.cam.ac.uk/consts/retrieving.html or can
be ordered from the following address: Cambridge Crystallographic Data
Centre, 12 Union Road, GB-Cambridge CB21EZ; fax: þ44 1223 336 033; or
deposit@ccdc.cam.ac.uk.