Tf2O-Mediated Cyclization of α-Acyl-β-(2-aminopyridinyl)acrylamides: Access to N-Substituted 4 H-Pyrido[1,2- a]pyrimidin-4-imines

Article abstract of DOI:10.1021/acs.joc.9b03495

A facile and efficient direct synthesis of N-substituted 4H-pyrido[1,2-a]pyrimidin-4-imines is developed from α-acyl-β-(2-aminopyridinyl)acrylamides mediated by triflic anhydride (Tf₂O) in the presence of 2-chloropyridine. This amide activation

Full text of DOI:10.1021/acs.joc.9b03495

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Article
Tf2O-mediated Cyclization of #-Acyl-#-(2-aminopyridinyl)acrylamides:
Access to N-Substituted 4H-Pyrido[1,2-a]pyrimidin-4-imines
Chitturi Bhujanga Rao, Ning Zhang, Jiana Hu, yu wang,
Yongjiu Liang, Rui Zhang, Jingwen Yuan, and Dewen Dong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03495 • Publication Date (Web): 09 Mar 2020
Downloaded from pubs.acs.org on March 10, 2020
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Tf2O-mediated Cyclization of
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α-Acyl-β-(2-aminopyridinyl)acrylamides: Access to
N-Substituted 4H-Pyrido[1,2-a]pyrimidin-4-imines
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Chitturi Bhujanga Rao,a Ning Zhang,a Jiana Hu,a,b Yu Wang,a,b Yongjiu Liang,a Rui
Zhang,*, a Jingwen Yuan,a and Dewen Dong*, a,b
a CAS Key Laboratory of High-Performance Synthetic Rubber and Its Composite
Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Changchun 130022, P. R. China
b University of Science and Technology of China, Hefei 230026, P. R. China
RECEIVED DATE (to be automatically inserted after your manuscript is accepted
if required according to the journal that you are submitting your paper to)
Abstract
R1
R3
R4
NHR1
HN
N
N
N
O
Tf2O/2-ClPy
rt, 15-25 min
R3
R4
O
O
R2
N
R2
Metal-free cyclization
Chemoselectivity
N-C bond formation
A facile and efficient direct synthesis of N-substituted 4H-pyrido[1,2-a]
pyrimidin-4-imines is developed from α-acyl-β-(2-aminopyridinyl)acrylamides mediated
by triflic anhydride (Tf2O) in the presence of 2-chloropyridine. This amide activation
protocol features mild reaction conditions, simple execution, excellent yields and high
chemoselectivity, and which is also applied to the synthesis of substituted 4H-pyrido
[1,2-a]pyrimidin-4-ones via a practical one-pot procedure.
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Introduction
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Over the past decades, pyrido[1,2-a]pyrimidines and their derivatives have emerged as
one of the most important N-fused bicyclic heterocycles since their presence in
numerous natural products and synthetic molecules along with a broad range of
bio-activities,1,2 and their diverse applications in pharmaceuticals, agrochemicals, and
advanced functional materials.3,4 In this family, pyrido[1,2-a]pyrimidin-4-ones have
been demonstrated to possess antiatherosclerotic, antipyretic, antipsychotic, antiallergic,
antidepressant, analgestic and analgesic properties,5,6 and some are now in clinical use.7
Their pharmacological importance has directed considerable research activity toward the
development of efficient synthetic approaches for such kind of heterocycles and
expanding their scope in the field of medicinal chemistry.8
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In contrast to extensive work on pyrido[1,2-a]pyrimidin-4-ones, however, there have
been fewer reports on pyrido[1,2-a]pyrimidin-4-imines, and most of them involves the
synthesis via condensation on the amidine fragment of 2-aminopyridine or its
derivatives with various functionalized acryl nitriles (Scheme 1A), allenic nitriles or
cyanoalkynes.5c,9 Guchhait and coworkers developed a novel three-component assembly
to fused pyrimidin-4-imines using a nitrile-stabilized ammonium ylide as a synthon.10
Wu and co-workers synthesized a series of pyrido[1,2-a]pyrimidin-4-imines via a formal
[3+3] cyclocondensation, and investigated their structure activity relationship as potent
5-HT6 antagonists.11 Recently, Namitharan and coworkers reported the direct synthesis
of N-substituted pyrido[1,2-a]pyrimidin-4-imines for the first time (Scheme 1B).12
Nevertheless, to match the increasing scientific and practical demand, the development
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of facile and efficient synthetic approaches to N-substituted 4H-pyrido[1,2-a]
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pyrimidin-4-imines is much more desired.
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Scheme 1. Construction of the Skeleton of Pyrido[1,2-a]pyrimidin-4-imines
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A) Formal [3+3] Cyclocondensation
NH
R1
CN
R1
R2
N
R3
N
+
R3
R2
H2N
SR/Cl
N
B) Copper(I)-Catalyzed Cascade Multicomponent Reactions
R2
O
S
R1
Ar
Cu (I)-zeolite
N
O
+
R1
N
O
TEA, CH2Cl2, rt
N
R2
S
N3
N
Ar
N
O
C) This work: Amide Activation Strategy
R1
NHR1
HN
N
R3
R4
N
N
O
Tf2O/2-ClPy
DCM, rt
R3
R4
O
O
R2
N
R2
Tf2O
R1
Cl
OTf
OTf
N H
HN
TfO
R1
N H
HN
R3
R4
N
N
R3
R4
2-ClPy
TfO
N
O
O
R2
R2
On the other hand, the electrophilic activation of amides with triflic anhydride in the
presence of varied pyridines have been extensively investigated for the synthesis of
piperidines, amines, pyridines, pyrimidines, and indoles in the last two decades.13,14
Notably, this amide activation strategy has been also applied to the concise synthesis of
some natural products.15 Inspired by these works and our continued research interest in
developing novel and efficient synthetic methods for highly valuable heterocycles from
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a variety of α-acylacrylamides,16 we set out to explore the reactions of α-acyl-β-(2-
aminopyridinyl)acrylamides mediated by triflic anhydride. After a series of detailed
investigations, we achieved a facile and efficient direct synthesis of N-substituted
4H-pyrido[1,2-a]pyrimidin-4-imines under very mild conditions (Scheme 1C). Herein,
we wish to report our experimental results.
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Results and Discussion
According to our reported procedure,17 a series of enaminones 1 was prepared from
commercially available β-oxoamides and N,N-dimethyl formamide dimethylacetal
(DMF-DMA) in the presence of K2CO3 in N,N-dimethyl formamide (DMF) in good
yields. Then, α-acyl-β-(2-aminopyridinyl)acrylamides 3 were prepared in high yields by
the reaction of 1 and 2-aminopyridines 2 in ethanol at reflux temperature (Scheme 2).
With acrylamides 3a-t in hand, we selected 3a as a model compound to examine its
reaction behavior toward triflic anhydride.
Scheme 2. Preparation of α-Acyl-β-(2-aminopyridinyl)acrylamides 3
R3
NHR1
HN
O
O
N
R3
R4
EtOH
N
O
O
NHR1
NHMe2
R2
R4
+
Reflux
H2N
R2
1
2
3
The reaction of 3a and Tf2O (1.2 equiv) was initially attempted in the presence of
pyridine (1.2 equiv) in dry dichloromethane (DCM) at room temperature for 12.0 h.
Unfortunately, no reaction was observed as indicated by TLC results (entry 1, Table 1),
and there was no significant change when the reaction mixture was heated to reflux
temperature (entry 2, Table 1). To our delight, by the employment of 2-methoxypyridine
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(1.2 equiv) as a base additive, the reaction of 3a and Tf2O proceeded sluggishly in DCM
at room temperature, which furnished a main product along with recovery of some
starting material 3a. The product was characterized as 1-{4-(phenylimino)-4H-
pyrido[1,2-a]pyrimidin-3yl}ethanone 4a on the basis of its spectral data (entry 3, Table
1).
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Table 1. Cyclization Reactions of 3a under Different Conditionsa
O
N
N
N
NH
HN
conditions
O
O
N
3a
4a
Entry
Tf2O
(equiv)
1.2
Additive
Temp
(oC)
rt
Time
(h)
Yieldb
(%)
(equiv)
1
Py (1.2)
12.0
12.0
12.0
12.0
12.0
12.0
12.0
6.0
0(95)
0(93)
34(49)
12(78)
10(75)
59(32)
65(16)
81(11)
84
2
1.2
Py (1.2)
reflux
3
1.2
2-MeOPy (1.2)
2-MePy (1.2)
4-MePy (1.2)
2-ClPy (1.2)
2-ClPy (1.2)
2-ClPy (1.5)
2-ClPy (1.5)
2-ClPy (1.8)
2-ClPy (2.0)
2-ClPy (2.0)
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
4
1.2
5
1.2
6
1.2
7
1.5
8
1.5
9
2.0
6.0
10
11
12
2.0
2.0
88
2.0
0.25
2.0
91
2.0
92
b
a Reagents and conditions: 3a (1.0 mmol), dry DCM (10 mL). Isolated yield for 4a
(data in the parentheses for the recovery of 3a).
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Encouraged by these findings, we then briefly examined the effect of different
additives, loaded amounts of additives and Tf2O, and temperature on the success of the
cyclization reaction of 3a, and some of the results are summarized in Table 1. Clearly,
2-chloropyridine was the most effective one among the tested additives to promote the
reaction of 3a (entries 3-6). As it was exemplified in different electrophilic activation of
amides mediated by Tf2O, the addition of some non-nucleophilic bases proved to be
essential, and 2-halopyridines were much suitable for this purpose.14c,18 Significantly,
the increase of loading amounts of Tf2O and/or 2-chloropyridine did accelerate the
reaction of 3a (entries 7-11). The conversion of 3a to 4a could be completed at 0 oC, but
it required a slightly prolonged time (entry 12). Therefore, the optimal reaction
conditions were obtained when 3a was treated with Tf2O (2.0 equiv) and
2-chloropyridine (2.0 equiv) in dry DCM at room temperature, whereby the yield of 4a
reached 91% (entry 11).
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With the optimal reaction conditions for the cyclization 3a in hand, we intended to
explore its scope and limitation with respect to the R1, R2 and R3 groups of acrylamides
3. As shown in Table 2, a series of reactions of acrylamides 3b-p bearing different
secondary N-aryl amide groups (CONHR1) and varied Me, MeO, Cl or NO2 substituents
R3 on their pyridine rings proceeded smoothly to afford the corresponding pyrido
[1,2-a]pyrimidin-4-imines 4b-p in excellent yields. Notably, the structure of 4b was
established by its spectra and analytical data, and unambiguously confirmed by its
single-crystal X-ray analysis (see supporting information). Similarly, 4q and 4r were
synthesized in fairly good yields from acrylamides 3q and 3r bearing N-benzyl- and
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N-alkyl amide groups, respectively. The versatility of this cyclization reaction was also
proved to be suitable for acryl amides 3s-u with aryl R2 groups to give the
corresponding pyrido[1,2-a]pyrimidin-4-imines 4s-u in quite high yields. The results
obtained above revealed that the Me, MeO, Cl or NO2 substituents on the phenyl or
pyridyl rings and the acyl or N-benzyl group of acrylamides 3 were well-tolerated under
the acidic cyclization conditions, and which demonstrated the efficiency and synthetic
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Table 2. Cyclization Reactions of Acrylamides 3a
R1
R3
R4
NHR1
HN
N
O
N
N
Tf2O/2-ClPy
DCM, rt
O
O
R3
R4
R2
N
R2
3
4
OMe
Cl
MeO
MeO
O
N
O
N
N
O
N
O
N
Cl
O
N
N
N
N
N
N
N
N
N
N
4e
4c
, 93%
4b
, 94%
, 96%
4d
, 92%
4f
, 95%
MeO
Cl
Cl
Cl
MeO
O
N
O
N
N
O
N
N
O
N
N
O
N
Cl
Cl
N
N
N
N
N
N
OMe
OMe
NO2
N
4j
, 84%
4i
4k
, 82%
4h
, 90%
, 91%
4g
, 96%
MeO
O
N
O
N
N
O
N
O
N
O
O
N
N
N
N
N
N
N
N
N
N
OMe
4p
, 82%
4l
4o
, 91%
, 78%
4n
4m
, 88%
, 91%
Cl
MeO
Cl
Cl
N
O
N
O
N
N
O
N
O
N
N
N
N
N
N
N
N
N
N
4q
, 75%
4s
4t
4r
, 89%
, 83%
, 68%
4u
, 88%
a Reagents and conditions: 3 (1.0 mmol), Tf2O (2.0 mmol), 2-chloropyridine (2.0 mmol),
dry DCM (10 mL), rt, 15-25 min. Isolated yields of 4 are given.
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value of the direct transformation of acrylamides 3 to N-substituted 4H-pyrido[1,2-a]
pyrimidin-4-imines 4. It is worth noting that the preferential activation of amide group
over its counterpart acyl group of acrylamide 3 in the present work exhibited high
chemoselectivity.
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Scheme 3. Gram-Scale Synthesis of 4H-Pyrido[1,2-a]pyrimidin-4-imine 4k
Cl
Cl
O
N
N
Tf2O, 2-ClPy
NH
HN
N
N
O
O
DCM, rt, 20 min
OMe
OMe
(5.0 mmol, 1.73 g)
4k
( 85%, 1.39 g)
3k
To further demonstrate utility, the cyclization of 3k was performed on a gram scale
under the optimal reaction conditions (Scheme 3). The reaction proceeded smoothly,
producing the corresponding 4H-pyrido[1,2-a]pyrimidin-4-imine 4k in 85% yield.
Therefore, we provided herein a facile and efficient protocol for the direct synthesis of
N-substituted 4H-pyrido[1,2-a]pyrimidin-4-imines of type 4.
Scheme 4. Hydrolysis of 4H-Pyrido[1,2-a]pyrimidin-4-imine 4a
O
O
HCl (aq., 3.0 N)
EtOH, 80 oC
O
N
N
N
N
N
5a
(89%)
4a
Consequently, we turned our attention to the application of this novel cyclization to
the synthesis of pyrido[1,2-a]pyrim-idin-4-ones. The hydrolysis of 4H-pyrido[1,2-a]
pyrimidin-4-imines was first attempted by subjecting 4a to an acidic aqueous solution at
room temperature, but no reaction was observed as indicated by TLC results. By
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increasing the temperature to 80 C, the reaction took place and furnished a product,
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which was characterized as 3-acetyl-8-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 5a on
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the basis of its spectral data (Scheme 4).
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Table 3. One-pot Synthesis of Pyrido[1,2-a]pyrimidin-4-ones 5 from Acrylamides 3a
NHR1
HN
O
O
N
4
N
R3
HCl (aq., 3.0 N)
EtOH, 80 oC
Tf2O/2-ClPy
DCM, rt
O
O
R3
R4
R2
N
R4
R2
5
3
2
3
1
2
3
4
5a
: R = Me; R = R = H; 81%
3a
: R = Ph; R = Me; R = R = H
2
4
3
1
2
4
3
5b
5c
: R = R = Me; R = H; 84%
3b
3g
3k
: R = 2-MeOC6H4; R = R = Me; R = H
2
4
3
1
2
4
3
: R = R = Me; R = Cl; 83%
: R = 2-MeOC6H4; R = R = Me; R = Cl
2
3
4
1
2
3
4
5d
: R = Me; R = H; R = MeO; 74%
: R = 4-ClC6H4; R = Me; R = H; R = MeO
2
3
4
1
2
3
4
5e
3t
: R = Ph; R = H; R = Me; 86%
: R = 2-ClC6H4; R = Ph; R = H; R = Me
2
3
4
1
2
3
4
5f
: R = Ph; R = Cl; R = Me; 85%
3u
: R = 4-ClC6H4; R = Ph; R = Cl; R = Me
a
Reagents and conditions: i) 3 (1.0 mmol), Tf2O (2.0 mmol), 2-chloropyridine (2.0
mmol), dry DCM (10 mL), rt, 15-25 min. ii) HCl (aq., 3.0 N, 5 mL), EtOH (5 mL), 80
oC, 5.5-6.5 h. Isolated yields of 5 are given.
These findings prompted us to explore the feasibility of in-situ hydrolysis
avoiding the isolation of 4H-pyrido[1,2-a]pyrimidin-4-imines 4. Thus, the reaction of 3a
and Tf2O was conducted under the optimal conditions as described in entry 11, Table 1.
Then, the solvent DCM was distilled off and a solution of aqueous HCl in ethanol was
o
reloaded to the reaction system, the resulting mixture was heated to 80 C and kept at
this temperature for 6.0 h, which finally afforded 5a in 81% yield (Table 3). In the same
fashion, a series of pyrido[1,2-a]pyrimidin-4-ones 5b-f were synthesized in high yields
via a one-pot procedure as shown in Table 3. The scalability of this in-situ hydrolysis
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transformation was investigated using 5.0 mmol of 3u as the starting material, to our
delight, the desired product 5f was obtained in 81% yield (1.21 g). These results show
the preparative utility of the one-pot synthesis of pyrido[1,2-a]pyrimidin-4-ones 5.
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Notably, the Gould-Jacobs reaction is a well-known reaction for the construction of
pyridine-4-one scaffolds, which is a classical thermal cyclization, typically requiring
temperatures more than 200 oC with prolonged heating and high-boiling solvent such as
diphenyl ether.19 In comparison to the Gould-Jacobs reaction, our present work provided
an alternative efficient synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones from
α-acyl-β-(2-aminopyridinyl)acrylamides under very mild conditions.
Conclusion
In summary, we have described herein an intramolecular cyclization of
α-acyl-β-(2-aminopyridinyl)acrylamides mediated by triflic anhydride in the presence of
2-chloropyridine. This amide activation transformation features mild reaction conditions,
simple execution, excellent yields and high chemoselectivity, thereby provides a facile
and efficient protocol for the direct synthesis of N-substituted 4H-pyrido[1,2-a]
pyrimidin-4-imines. In addition, the synthesis of substituted 4H-pyrido[1,2-a]
pyrimidin-4-ones has also been achieved directly from α-acyl-β-(2-aminopyridinyl)
acrylamides via a practical one-pot procedure. Further studies on the mechanism
involved in the reactions and the utilization and extension of the scope of the protocols
are currently underway in our laboratory
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EXPERIMENTAL SECTION
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General Experimental
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All reagents were purchased from commercial sources and used without treatment,
unless otherwise indicated. The products were purified by column chromatography over
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silica gel. H NMR and C NMR spectra were recorded at 25 C at 300 MHz (or 400
MHz) and 75 MHz (or 100 MHz), respectively, with TMS as internal standard. IR
spectra (KBr) were recorded on FTIR-spectrophotometer in the range of 400-4000 cm-1.
High resolution mass spectra (HRMS) were recorded on a mass spectrometer (ESI-
LTQ-Orbitrap). Melting points were recorded on a TECH X-4 micro-melting point
apparatus. All reactions were monitored by TLC with GF254 silica gel-coated plates.
The products were isolated by column chromatography on silica gel (300−400 mesh).
General Procedure A for the Synthesis of α-Acyl-β-(2-aminopyridinyl)acrylamides
3 (3a as an example): To a solution of 1a (1.16 g, 5.0 mmol) in ethanol (25 mL) was
added 2-aminopyridine 2a (0.52 g, 5.5 mmol) under stirring. The resulting mixture was
heated at reflux temperature for 6.0 h, and then cooled down to room temperature. A
white solid was precipitated from the reaction system, which was collected by filtration,
washed with cold ethanol/water (2:1, v/v), and dried in vacuo to give 3a (1.26 g, 90%).
Analytical Data of α-Acyl-β-(2-aminopyridinyl)acrylamides 3
3-Oxo-N-phenyl-2-((pyridin-2-ylamino)methylene)butanamide (3a): White solid
(1.26 g, 90%), mp 124-125 oC; 1H NMR (300 MHz, CDCl3): δ 2.53 (s, 3H), 6.93 (d, J =
8.1 Hz, 1H), 7.06-7.14 (m, 2H), 7.35 (t, J = 7.8 Hz, 2H), 7.62 (d, J = 7.8 Hz, 2H), 7.69 (t,
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J = 7.8 Hz, 1H), 8.37 (d, J = 4.8 Hz, 1H), 9.27 (d, J = 11.7 Hz, 1H), 11.75 (s, 1H), 12.82
(d, J = 11.7 Hz, 1H); 13C{H}NMR (75 MHz, CDCl3): δ 26.6, 105.2, 112.9, 120.0, 120.8
(2C), 124.0, 128.8 (2C), 138.0, 138.7, 148.5, 150.1, 151.2, 167.0, 197.7; IR (KBr): ν =
3049, 2997, 1652, 1588, 1537,1490, 1378, 1314, 759 cm-1; HRMS (ESI) calcd for
C16H16N3O2 [M+H]+: 282.1237, found: 282.1235.
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N-(2-Methoxyphenyl)-2-(((4-methylpyridin-2-yl)amino)methylene)-3-oxobutanami
de (3b): White solid (1.56 g, 96%), mp 187-188 oC; 1H NMR (300 MHz, CDCl3): δ 2.36
(s, 3H), 2.53 (s, 3H), 3.97 (s, 3H), 6.77 (s, 1H), 6.86-7.10 (m, 4H), 8.21 (d, J = 5.1 Hz,
1H), 8.42 (dd, J1 = 7.8 Hz, J2 = 1.5 Hz, 1H), 9.24 (d, J = 12.0 Hz, 1H), 12.03 (s, 1H),
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12.79 (d, J = 11.4 Hz, 1H); C{H}NMR (75 MHz, CDCl3): δ 21.0, 26.5, 55.8, 105.6,
110.1, 113.5, 120.6, 120.6, 121.2, 123.5, 128.1, 148.1, 149.2, 150.2, 150.4, 151.2, 166.9,
197.4; IR (KBr): ν = 3138, 2971, 2939, 1645, 1610, 1528, 1486, 1325, 1260, 760 cm-1;
HRMS (ESI) calcd for C18H19N3NaO3 [M+Na]+: 348.1319, found: 348.1314.
N-(4-Methoxyphenyl)-2-(((4-methylpyridin-2-yl)amino)methylene)-3-oxobutan-
amide (3c): White solid (1.55 g, 95%), mp 125-126 oC; 1H NMR (300 MHz, CDCl3): δ
2.35 (s, 3H), 2.51 (s, 3H), 3.81 (s, 3H), 6.74 (s, 1H), 6.88-6.91 (m, 3H), 7.52 (d, J = 9.0
Hz, 2H), 8.21 (d, J = 5.1 Hz, 1H), 9.24 (d, J = 12.0 Hz, 1H), 11.60 (s, 1H), 12.79 (d, J =
13
11.1 Hz, 1H); C{H}NMR (75 MHz, CDCl3): δ 21.0, 26.6, 55.4, 105.0, 113.5, 114.0
(2C), 121.2, 122.5 (2C), 131.1, 148.1, 150.2, 150.3, 151.3, 156.1, 166.9, 197.6; IR (KBr):
ν = 3131, 2981, 2929, 1645, 1607, 1547, 1463, 1341, 1208, 768 cm-1; HRMS (ESI)
calcd for C18H19N3NaO3 [M+Na]+: 348.1319, found: 348.1323.
N-(4-Chlorophenyl)-2-(((4-methylpyridin-2-yl)amino)methylene)-3-oxobutanamide
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(3d): White solid (1.53 g, 93%), mp 169-170 oC; 1H NMR (300 MHz, CDCl3): δ 2.36 (s,
3H), 2.52 (s, 3H), 6.76 (s, 1H), 6.91 (d, J = 5.1 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H), 7.59 (d,
J = 8.7 Hz, 2H), 8.22 (d, J = 5.1 Hz, 1H), 9.25 (d, J = 11.7 Hz, 1H), 11.83 (s, 1H), 12.69
(d, J = 11.4 Hz, 1H); 13C NMR{H}(75 MHz, CDCl3): δ 21.0, 26.5, 104.7, 113.5, 121.4,
121.8 (2C), 128.6, 128.8 (2C), 136.8, 148.1, 150.1, 150.3, 151.5, 170.0, 197.6; IR (KBr):
ν = 3106, 2971, 2939, 1638, 1621, 1529, 1473, 1422, 1358, 1209, 1127, 664 cm-1;
HRMS (ESI) calcd for C17H16ClN3NaO2 [M+Na]+: 352.0823, found: 352.0822.
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2-(((4-Methylpyridin-2-yl)amino)methylene)-3-oxo-N-phenylbutanamide
(3e):
White solid (1.37 g, 93%), mp 136-137 oC; 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 3H),
2.52 (s, 3H). 6.76 (s, 1H), 6.90 (d, J = 5.1 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.35 (t, J =
7.8 Hz, 2H), 7.63 (d, J = 7.8 Hz, 2H), 8.22 (d, J = 5.1 Hz, 1H), 9.25 (d, J = 11.7 Hz, 1H),
11.76 (s, 1H), 12.76 (d, J = 11.4 Hz, 1H); 13C{H}NMR (75 MHz, CDCl3): δ 21.0, 26.6,
105.0, 113.5, 120.8 (2C), 121.3, 123.9, 128.8 (2C), 138.1, 148.1, 150.2, 150.3, 151.5,
167.1, 197.6; IR (KBr): ν = 3054, 2928, 1666, 1629, 1582, 1463, 1275, 1100, 764 cm-1;
HRMS (ESI) calcd for C17H17N3NaO2 [M+Na]+: 318.1213, found: 318.1217.
N-(5-Chloro-2-methoxyphenyl)-2-(((4-methylpyridin-2-yl)amino)methylene)-3-oxo-
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butanamide (3f): White solid (1.72 g, 96%), mp 235-236 C; H NMR (300 MHz,
CDCl3): δ 2.37 (s, 3H), 2.52 (s, 3H), 3.95 (s, 3H), 6.80 (s, 1H), 6.81 (d, J = 8.4 Hz, 1H),
6.91 (d, J = 4.8 Hz, 1H), 7.00 (dd, J1 =8.7 Hz, J2 = 2.4 Hz, 1H), 8.22 (d, J = 5.1 Hz, 1H),
8.54 (d, J = 2.4 Hz, 1H), 9.25 (d, J = 12.0 Hz, 1H), 12.10 (s, 1H), 12.73 (d, J = 12.0 Hz,
1H); 13C NMR{H}(75 MHz, CDCl3): δ 21.0, 26.5, 56.1, 105.3, 110.7, 113.6, 120.2,
121.3, 122.7, 125.6, 129.2, 147.6, 148.1, 150.2, 150.3, 151.4, 167.0, 197.4; IR (KBr): ν
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= 3136, 3028, 2974, 2916, 1655, 1611, 1534, 1453, 1379, 1215, 768, 662 cm-1; HRMS
(ESI) calcd for C18H18ClN3NaO3 [M+Na]+: 382.0929, found: 382.0935.
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butanamide (3g): White solid (1.69 g, 94%), mp 213-214 C; H NMR (300 MHz,
CDCl3): δ 2.38 (s, 3H), 2.52(s, 3H), 3.97 (s, 3H), 6.83 (s, 1H), 6.91-6.99 (m, 2H), 7.07 (t,
J = 7.8 Hz, 1H), 8.24 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 9.14 (d, J = 11.7 Hz, 1H), 11.99
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(s, 1H), 12.87 (d, J = 11.7 Hz, 1H); C{H}NMR (75 MHz, CDCl3): δ 19.6, 26.5, 55.8,
105.9, 110.1, 114.3, 120.5, 120.6, 123.6, 127.9, 127.9, 147.0, 147.8, 148.7, 149.1, 150.8,
166.7, 197.3; IR (KBr): ν = 3144, 3012, 2982, 2938, 1654, 1613, 1519, 1425, 1264,
1108, 788 cm-1; HRMS (ESI) calcd for C18H18ClN3NaO3 [M+Na]+: 382.0929, found:
382.0930.
2-(((5-Chloro-4-methylpyridin-2-yl)amino)methylene)-N-(4-chlorophenyl)-3-oxo-
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butanamide (3h): White solid (1.67 g, 92%), mp 199-200 C; H NMR (300 MHz,
CDCl3): δ 2.39 (s, 3H), 2.51 (s, 3H), 6.83 (s, 1H), 7.30 (d, J = 8.7 Hz, 2H), 7.57 (d, J =
8.7 Hz, 2H), 8.25 (s, 1H), 9.16 (d, J = 11.7 Hz, 1H), 11.80 (s, 1H), 12.76 (d, J = 11.7 Hz,
1H); 13C{H}NMR (75 MHz, CDCl3): δ 19.7, 26.6, 105.2, 114.4, 121.8 (2C), 128.3,
128.8 (3C), 136.6, 147.2, 148.0, 148.5, 151.3, 166.9, 197.7; IR (KBr): ν = 3062, 2973,
2931, 2893, 1664, 1600, 1545, 1454, 1367, 1212, 669 cm-1; HRMS (ESI) calcd for
C17H15Cl2N3NaO2 [M+Na]+: 386.0434, found: 386.0440.
2-(((5-Chloro-4-methylpyridin-2-yl)amino)methylene)3-oxo-N-phenylbutanamide
(3i): White solid (1.56 g, 95%), mp 171-173 oC; 1H NMR (300 MHz, CDCl3): δ 2.39 (s,
3H), 2.52 (s, 3H), 6.82 (s, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.62 (d,
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Hz, 1H); 13C{H}NMR (75 MHz, CDCl3): δ 19.7, 26.6, 105.4, 114.4, 120.8 (2C), 124.0,
128.1, 128.8 (2C), 138.0, 147.1, 147.9, 148.6, 151.1, 166.9, 197.6; IR (KBr): ν = 3046,
2983, 1658, 1595, 1547, 1492, 1324 1242, 1033, 752 cm-1; HRMS (ESI) calcd for
C17H16ClN3NaO2 [M+Na]+: 352.0823, found: 352.0828.
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N-(4-Methoxyphenyl)-2-(((4-methoxypyridin-2-yl)amino)methylene)-3-oxobutanam
ide (3j): White solid (1.57 g, 92%), mp 217-218 oC; 1H NMR (400 MHz, CDCl3): δ 2.52
(s, 3H), 3.86 (s, 3H), 3.96 (s, 3H), 6.43 (s, 1H), 6.62 (dd, J = 2.0 Hz, 5.6 Hz, 1H),
6.89-7.01 (m, 2H), 7.06 (t, J = 7.2 Hz, 1H), 8.16 (d, J = 6.0 Hz, 1H), 8.40 (d, J = 8.0 Hz,
1H), 9.24 (d, J = 12.0 Hz, 1H), 12.01 (s, 1H), 12.80 (d, J = 11.6 Hz, 1H); 13C{H}NMR
(75 MHz, CDCl3): δ 26.6, 55.4, 55.9, 97.9, 105.6, 107.7, 110.2, 120.6 (2C), 123.7, 128.0,
149.3, 149.4, 151.3, 152.0, 166.9, 167.7, 197.5; IR (KBr): ν = 3119, 2996, 2932, 1661,
1618, 1515, 1478, 1436, 1238, 1138, 776 cm-1; HRMS (ESI) calcd for C18H19N3NaO4
[M+Na]+: 364.1268, found: 364.1266.
N-(4-Chlorophenyl)-2-(((4-methoxypyridin-2-yl)amino)methylene)-3-oxobutanamid
e (3k): White solid (1.55 g, 90%), mp 195-196 oC; 1H NMR (300 MHz, CDCl3): δ 2.52
(s, 3H), 3.87 (s, 3H), 6.42 (s, 1H), 6.64 (d, J = 5.7 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H),
7.58 (d, J = 8.7 Hz, 2H), 8.17 (d, J = 5.7 Hz, 1H), 9.26 (d, J = 11.7 Hz, 1H), 11.83 (s,
1H), 12.70 (d, J = 11.4 Hz, 1H); 13C{H}NMR (75 MHz, CDCl3): δ 26.6, 55.4, 97.8,
104.8, 107.8, 121.9 (2C), 128.8, 128.8 (2C), 136.7, 149.5, 151.7, 151.7, 167.1, 167.8,
197.7; IR (KBr): ν = 3064, 2971, 1654, 1591, 1473, 1428, 1308, 1263, 1158, 752 cm-1;
HRMS (ESI) calcd for C17H16ClN3NaO3 [M+Na]+: 368.0772, found: 368.0774.
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2-(((4-Methoxypyridin-2-yl)amino)methylene)-3-oxo-N-phenylbutanamide (3l):
White solid (1.41g, 91%), mp 147-148 oC; 1H NMR (300 MHz, CDCl3): δ 2.52 (s, 3H),
3.86 (s, 3H), 6.42 (d, J = 1.8 Hz, 1H), 6.63 (dd, J1 =5.7 Hz, J2 = 2.1 Hz,1H), 7.11 (t, J =
7.5 Hz, 1H), 7.35 (t, J = 7.8 Hz, 2H), 7.62 (d, J = 7.8 Hz, 2H), 8.16 (d, J = 5.7 Hz, 1H),
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9.25 (d, J = 11.7 Hz, 1H), 11.76 (s, 1H), 12.78 (d, J = 11.1 Hz, 1H); C{H}NMR (75
MHz, CDCl3): δ 26.6, 55.4, 97.7, 105.0, 107.7, 120.9 (2C), 124.0, 128.8 (2C), 138.0,
149.4, 151.6, 151.8, 167.1, 167.7, 197.7; IR (KBr): ν = 3028, 2948, 2894, 1652, 1624,
1576, 1565, 1389, 1326, 1015, 788 cm-1; HRMS (ESI) calcd for C17H17N3NaO3
[M+Na]+: 334.1162, found: 334.1159.
2-(((3-Methylpyridin-2-yl)amino)methylene)-3-oxo-N-phenylbutanamide
(3m):
White solid (1.30 g, 88%), mp 182-183 oC; 1H NMR (300 MHz, CDCl3): δ 2.41 (s, 3H),
2.54 (s, 3H), 6.99-7.03 (m, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.8 Hz, 2H), 7.53 (d,
J = 7.5 Hz, 1H), 7.66 (d, J = 7.8 Hz, 2H), 8.22 (d, J = 4.5 Hz, 1H), 9.33 (d, J = 11.7 Hz,
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1H), 11.8 (s, 1H), 13.07 (d, J = 11.1 Hz, 1H); C{H}NMR (75 MHz, CDCl3): δ 16.5,
26.7, 105.4, 119.9, 120.8 (2C), 121.1, 123.8 (2C), 128.8, 138.1, 139.4 145.9, 148.9,
151.4, 167.2, 195.9, 197.7; IR (KBr): ν = 3056, 2969, 2938, 1646, 1611, 1585, 1515,
1465, 1267, 1158, 768 cm-1; HRMS (ESI) calcd for C17H17N3NaO2 [M+Na]+: 318.1213,
found: 318.1208.
N-(2-Methoxyphenyl)-3-oxo-2-((pyridin-2-ylamino)methylene)butanamide
(3n):
White solid (1.46g, 94%), mp 148-149 oC; 1H NMR (300 MHz, CDCl3): δ 2.54 (s, 3H),
3.97 (s, 3H), 6.91-7.01 (m, 3H), 7.04-7.09 (m, 2H), 7.69 (td, J1 =7.8 Hz, J2 = 1.8 Hz,
1H), 8.36-8.42 (m, 2H), 9.26 (d, J = 11.7 Hz, 1H), 12.02 (s, 1H), 12.84 (d, J = 11.7 Hz,
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1H); C{H}NMR (100 MHz, CDCl3): δ 26.5, 55.9, 105.9, 110.2, 112.9, 119.8, 120.7
(2C), 123.7, 128.1, 138.7, 148.6, 149.3, 150.3, 151.0, 166.9, 197.4; IR (KBr): ν = 3120,
3008, 2935, 2873. 1634, 1614, 1529, 1467, 1412, 1326, 1146, 748 cm-1; HRMS (ESI)
calcd for C17H17N3NaO3 [M+Na]+: 334.1162, found: 334.1165.
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3-Oxo-2-((pyridin-2-ylamino)methylene)-N-(p-tolyl)butanamide (3o): White solid
(1.34 g, 91%), mp 129-130 oC; 1H NMR (300 MHz, CDCl3): δ 2.33 (s, 3H), 2.52 (s, 3H),
6.92 (d, J = 8.1 Hz, 1H), 7.07 (dd, J1 = 6.9 Hz, J2 = 5.1 Hz, 1H), 7.15 (d, J = 8.1 Hz, 2H),
7.50 (d, J = 8.1 Hz, 2H), 7.68 (t, J = 7.8 Hz, 1H), 8.37 (d, J = 4.8 Hz, 1H), 9.26 (d, J =
12.0 Hz, 1H), 11.66 (s, 1H), 12.83 (d, J = 11.7 Hz, 1H); 13C{H}NMR (75 MHz, CDCl3):
δ 20.9, 26.6, 105.3, 112.9, 119.9, 120.9 (2C), 129.4 (2C), 133.6, 135.4, 138.7, 148.5,
150.2, 151.1, 166.9, 197.7; IR (KBr): ν = 3044, 2971, 2920, 1654, 1608, 1590, 1514,
1442, 1296, 1216, 1110, 799 cm-1; HRMS (ESI) calcd for C17H17N3NaO2 [M+Na]+:
318.1213, found: 318.1211.
N-(3-Nitrophenyl)-3-oxo-2-((pyridin-2-ylamino)methylene)butanamide (3p): White
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solid (1.30 g, 79%), mp 211-213 C; H NMR (300 MHz, CDCl3): δ 2.55 (s, 3H), 7.00
(d, J = 8.4 Hz, 1H), 7.12 (dd, J1 = 6.9 Hz, J2 = 5.1 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H),
7.69-7.83 (m, 2H), 7.95 (dd, J1 = 8.1 Hz, J2 = 1.5 Hz, 1H), 8.39 (d, J = 3.9 Hz, 1H), 8.78
(t, J = 2.1 Hz, 1H), 9.32 (d, J = 12.0 Hz, 1H) 12.14 (s, 1H), 12.68 (d, J = 12.0 Hz, 1H);
13C{H}NMR (75 MHz, CDCl3): δ 26.6, 104.6, 113.1, 115.3, 118.3, 120.4, 126.0, 129.4,
138.9, 139.4, 148.5, 148.7, 149.9, 151.8, 167.4, 197.9; IR (KBr): ν = 3106, 3037, 2969,
2861, 1613, 1530, 1455, 1405, 1243, 1031, 868, 677 cm-1; HRMS (ESI) calcd for
C16H14N4NaO4 [M+Na]+: 349.0907, found: 349.0912.
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N-Benzyl-3-oxo-2-((pyridin-2-ylamino)methylene)butanamide (3q): White solid
(1.24 g, 84%), mp 126-127 oC; 1H NMR (300 MHz, CDCl3): δ 2.47 (s, 3H), 4.57 (d, J =
5.7 Hz, 2H), 6.88 (d, J = 8.1 Hz, 1H), 7.03-7.07 (m, 1H), 7.26-7.38 (m, 5H), 7.66 (t, J =
7.8 Hz, 1H), 8.35 (d, J = 4.8 Hz, 1H), 9.19 (d, J = 11.7 Hz, 1H), 10.06 (s, 1H), 12.84 (d,
J = 11.4 Hz, 1H); 13C{H}NMR (75 MHz, CDCl3): δ 26.5, 42.5, 105.1, 112.8, 119.7,
127.0, 127.2 (2C), 128.5 (2C), 138.5, 138.6, 148.4, 150.3, 150.6, 168.8, 197.4; IR (KBr):
ν = 3269, 2934, 2917, 1630, 1593, 1528, 1473, 1318, 1256, 1142, 729 cm-1; HRMS (ESI)
calcd for C17H17N3NaO2 [M+Na]+: 318.1213, found: 318.1216.
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N-Butyl-3-oxo-2-((pyridin-2-ylamino)methylene)butanamide (3r): White solid (1.03
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g, 79%), mp 103-104 C. H NMR (300 MHz, CDCl3): δ 0.95 (t, J = 7.2 Hz, 3H),
1.35-1.48 (m, 2H), 1.53-1.63 (m, 2H), 2.46 (s, 3H), 3.35 (q, J = 6.3 Hz, 2H), 6.87 (d, J =
8.1 Hz, 1H), 7.04 (t, J = 5.1 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 8.34 (d, J = 4.8 Hz, 1H),
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9.16 (d, J = 11.4 Hz, 1H), 9.64 (s, 1H), 12.93 (d, J = 11.7 Hz, 1H); C{H}NMR (75
MHz, CDCl3): δ 13.7, 20.3, 26.5, 31.5, 38.4, 105.3, 112.8, 119.6, 138.6, 148.4, 150.4,
150.5, 168.7, 197.4; IR (KBr): ν = 3264, 2951, 2935, 1643, 1594, 1473, 1319, 1255, 981,
777 cm-1; HRMS (ESI) calcd for C14H19N3NaO2 [M+Na]+: 284.1369, found: 284.1370.
2-Benzoyl-N-(2-methoxyphenyl)-3-(pyridin-2-ylamino)acrylamide (3s): White solid
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(1.77 g, 95%), mp 202-203 C; H NMR (300 MHz, CDCl3): δ 3.99 (s, 3H), 6.91-7.11
(m, 5H), 7.46-7.59 (m, 3H), 7.62-7.68 (m, 3H), 8.21 (d, J = 4.8 Hz, 1H), 8.47 (d, J = 7.8
Hz, 1H), 8.92 (d, J = 12.0 Hz, 1H), 11.99 (s, 1H), 11.85 (d, J = 11.7 Hz, 1H);
13C{H}NMR (75 MHz, CDCl3): δ 55.9, 105.0, 110.2, 112.7, 119.8, 120.6, 120.6, 123.7,
127.9, 128.3 (2C), 128.8 (2C), 130.9, 138.5, 140.1, 148.6, 149.2, 150.1, 154.1, 167.1,
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197.0; IR (KBr): ν = 3059, 2940, 1633, 1587, 1538, 1447, 1313, 1254, 747 cm-1; HRMS
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(ESI) calcd for C22H20N3O3 [M+H]+: 374.1499, found: 374.1497.
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2-Benzoyl-N-(2-chlorophenyl)-3-((4-methylpyridin-2-yl)amino)acrylamide
(3t):
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White solid (1.86 g, 95%), mp 208-209 oC; 1H NMR (300 MHz, CDCl3): δ 2.34, (s, 3H),
6.76 (s, 1H), 6.85 (d, J = 5.1 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 2H),
7.43-7.58 (m, 4H), 7.65 (d, J = 8.1 Hz, 2H), 8.08 (d, J = 5.1 Hz, 1H), 8.49 (d, J = 8.1 Hz,
1H), 8.97 (d, J = 12.3 Hz, 1H), 12.16 (s, 1H), 12.68 (d, J = 11.7 Hz, 1H); 13C{H}NMR
(75 MHz, CDCl3): δ 21.0, 104.3, 113.4, 121.4, 122.3, 124.3, 124.3, 127.1, 128.4 (2C),
129.0 (2C), 129.4, 131.1, 135.5, 139.8, 148.3, 150.1, 150.2, 154.6, 167.5, 196.9; IR
(KBr): ν = 3052, 2940, 1633, 1611, 1592, 1534, 1463, 1339, 1242, 782, 664 cm-1;
HRMS (ESI) calcd for C22H18ClN3NaO2 [M+Na]+: 414.0980, found: 414.0978.
2-Benzoyl-3-((5-chloro-4-methylpyridin-2-yl)amino)-N-(4-chlorophenyl)acrylamide
(3u): White solid (1.98g, 93%), mp 247-248 oC; 1H NMR (300 MHz, CDCl3): δ 2.37 (s,
3H), 6.82 (s, 1H), 7.33 (d, J = 8.7 Hz, 2H), 7.43-7.48 (m, 1H), 7.51 (d, J = 7.5 Hz, 2H),
7.57-7.65 (m, 4H), 8.11 (s, 1H), 8.84 (d, J = 12.0 Hz, 1H), 11.79 (s, 1H), 12.75 (d, J =
13
11.7 Hz, 1H); C{H}NMR (75 MHz, CDCl3): δ 19.7, 104.4, 114.4, 121.9 (2C), 128.3,
128.4 (2C), 128.8 (2C), 128.9 (2C), 129.0, 131.2, 136.6, 139.7, 147.3, 147.9, 148.4,
154.4, 167.2, 197.0; IR (KBr): ν = 3118, 1688, 1601, 1592, 1545, 1474, 1212, 752, 700
cm-1; HRMS (ESI) calcd for C22H17Cl2N3NaO2 [M+Na]+: 448.0590, found: 448.0593.
General Procedure B for the Synthesis of N-Substituted 4H-Pyrido-[1,2-a]
pyrimidin-4-imines 4 (4a as an example): To a solution of 3a (281 mg,1.0 mmol) and
triflic anhydride (564 mg, 2.0 mmol) in DCM (5 mL) was added a solution of
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2-chloropyridine (227 mg, 2.0 mmol) in DCM (5 mL) dropwise within 10 min. After
stirring at room temperature for 15 min, the resulting mixture was poured onto crushed
ice and neutralized with saturated aqueous NaHCO3, and then extracted with DCM (3 ×
15 mL). The combined organic layer was washed with water (3 × 25 mL), dried over
anhydrous Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by
flash column chromatography on silica gel using petroleum ether and ethyl acetate as the
eluent (3:2, v/v) to give 4a as a reddish yellow solid (240 mg, 91%).
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Analytical Data of N-Substituted 4H-Pyrido[1, 2-a]pyrimidin-4-imines (4)
1-(4-(Phenylimino)-4H-pyrido[1,2-a]pyrimid-in-3-yl)ethanone (4a): Prepared from
3a (281 mg, 1.0 mmol) according to the general procedure B. The crude product was
purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate as the
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eluent = 3:2) to give 4a as a reddish yellow solid (240 mg, 91%). mp 154-155 C; H
NMR (300 MHz, CDCl3): δ 1.84 (s, 3H), 6.91 (d, J = 7.5 Hz, 2H), 7.01 (t, J = 7.5 Hz,
1H), 7.14 (td, J1 =7.2 Hz, J2 = 1.3 Hz, 1H), 7.30 (t, J = 8.1 Hz, 2H), 7.54 (d, J = 8.4 Hz,
1H), 7.79 (m, 1H), 8.18 (s, 1H), 9.54 (d, J = 6.6 Hz, 1H); 13C NMR{H}(75 MHz,
CDCl3): δ. 28.3, 114.4, 115.8, 119.5 (2C), 123.1, 125.9, 129.6 (3C), 138.1, 144.5, 148.9,
152.5, 153.4, 196.3. IR (KBr): ν = 3123, 3031, 2943, 1679, 1615, 1584, 1492, 1348,
1237, 1120, 775 cm-1; HRMS (ESI) calcd for C16H14N3O [M+H]+: 264.1131, found:
264.1129.
1-(4-((2-Methoxyphenyl)imino)-8-methyl-4H-pyrido[1, 2-a]pyrimidin-3-yl)ethanone
(4b): Prepared from 3b (325 mg, 1.0 mmol) according to the general procedure B. The
crude product was purified by flash column chromatography (silica gel, petroleum
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ether/ethyl acetate as the eluent = 3:2) to give 4b as a reddish yellow solid (295 mg,
96%). mp 173-175 oC; 1H NMR (300 MHz, CDCl3): δ 1.89 (s, 3H), 2.49 (s, 3H), 3.80 (s,
3H), 6.85-7.03 (m, 5H), 7.31 (s, 1H), 8.16 (s, 1H), 9.52 (d, J = 7.2 Hz, 1H);
13C{H}NMR (100 MHz, CDCl3): δ 21.3, 27.7, 55.2, 111.3, 114.8, 118.1, 120.3, 121.1,
123.7, 124.1, 129.3, 137.8, 143.9, 150.0, 150.2, 152.1, 152.5, 195.5; IR (KBr): ν = 3022,
2968, 2912, 2854, 1645, 1620, 1584, 1511, 1438, 1296, 1176, 1018, 760 cm-1; HRMS
(ESI) calcd for C18H18N3O2 [M+H]+: 308.1394, found: 308.1397.
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Crystal Data for 4b: C18H17N3O2, Yellow crystal, M = 307.35, orthorhombic, pbca,
a =13.2254 (3) Ǻ, b = 7.5242 (2) Ǻ, c = 30.3701(8) Ǻ, α = β = γ = 90.00o, V = 3022.15
(13) Ǻ3, Z = 8, T = 190 K, F000 = 1296.0, R = 0.0372 (2455), wR2 = 0.0998
(2660). CCDC 1955119 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/ data_request/cif.
1-(4-((4-Methoxyphenyl)imino)-8-methyl-4H-pyrido[1,2 -a]pyrimidin-3-yl)ethanone
(4c): Prepared from 3c (325 mg, 1.0 mmol) according to the general procedure B. The
crude product was purified by flash column chromatography (silica gel, petroleum
ether/ethyl acetate as the eluent = 3:2) to give 4c as a reddish yellow solid (288 mg,
94%). mp 136-138 oC; 1H NMR (300 MHz, CDCl3): δ 1.85 (s, 3H), 2.49 (s, 3H), 3.78 (s,
3H), 6.85 (s, 4H), 6.95 (dd, J1 =7.5 Hz, J2 = 1.5 Hz, 1H), 7.29 (d, J = 4.8 Hz, 1H), 8.14
13
(s, 1H), 9.39 (d, J = 7.5 Hz, 1H); C{H}NMR (75 MHz, CDCl3): δ 21.3, 28.3, 55.3,
113.7, 114.8 (2C), 118.3, 120.5 (2C), 124.0, 128.9, 142.2, 144.6, 150.7, 152.3, 153.7,
155.4, 196.4; IR (KBr): ν = 3018, 2928, 2893, 2832, 1652, 1616, 1530, 1446, 1322,
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1246, 1129, 768 cm-1; HRMS (ESI) calcd for C18H17N3NaO2 [M+Na]+: 330.1213, found:
330.1217.
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1-(4-((4-Chlorophenyl)imino)-8-methyl-4H-pyrido[1,2-a]pyrimidin-3-yl)ethanone
(4d): Prepared from 3d (330 mg, 1.0 mmol) according to the general procedure B. The
crude product was purified by flash column chromatography (silica gel, petroleum
ether/ethyl acetate as the eluent = 3:2) to give 4d as a reddish yellow solid (286 mg,
92%). mp 124-125 oC; 1H NMR (300 MHz, CDCl3): δ 1.94 (s, 3H), 2.51 (s, 3H), 6.82 (d,
J = 8.7 Hz, 2H), 6.99 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H), 7.34 (s, 1H), 8.22 (s,
1H), 9.41 (d, J = 7.2 Hz, 1H). 13C{H}NMR (75 MHz, CDCl3): δ 21.4, 28.2, 113.0, 118.7,
120.7 (2C), 124.3, 127.7, 128.9, 129.5 (2C), 144.8, 147.9, 151.0, 152.2, 154.4, 195.8; IR
(KBr): ν = 3012, 2968, 2928, 2873, 1640, 1620, 1545, 1516, 1447, 1358, 1212, 1100,
686 cm-1; HRMS (ESI) calcd for C17H15ClN3O [M+H]+: 312.0898, found: 312.0893.
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1-(8-Methyl-4-(phenylimino)-4H-pyrido[1,2-a]pyramid-in-3-yl)ethanone
(4e):
Prepared from 3e (295 mg, 1.0 mmol) according to the general procedure B. The crude
product was purified by flash column chromatography (silica gel, petroleum ether/ethyl
acetate as the eluent = 3:2) to give 4e as a reddish yellow solid (256 mg, 93 %). mp
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167-169 C; H NMR (300 MHz, CDCl3): δ 1.83 (s, 3H), 2.50 (s, 3H), 6.90 (d, J = 7.5
Hz, 2H), 6.96-7.02 (m, 2H), 7.27-7.32 (m, 3H), 8.17 (s, 1H), 9.43 (d, J = 7.5 Hz, 1H);
13C{H}NMR (75 MHz, CDCl3): δ 21.4, 28.3, 113.5, 118.4, 119.5 (2C), 123.0, 124.2,
128.9, 129.5 (2C), 144.6, 149.1, 150.7, 152.3, 154.0, 196.3; IR (KBr): ν = 3108, 2968,
2874, 1680, 1606, 1545, 1498, 1452, 1347, 1225, 1104, 782 cm-1; HRMS (ESI) calcd for
C17H16N3O [M+H]+: 278.1288, found: 278.1290.
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1-(4-((5-Chloro-2-methoxyphenyl)imino)-8-methyl-4H-pyrido[1,2-a]pyrimidin-3-yl)
ethanone (4f): Prepared from 3f (360 mg, 1.0 mmol) according to the general procedure
B. The crude product was purified by flash column chromatography (silica gel,
petroleum ether/ethyl acetate as the eluent = 3:2) to give 4f as a reddish yellow solid
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(324 mg, 95%). mp 158-160 C; H NMR (300 MHz, CDCl3): δ 2.06 (s, 3H), 2.50 (s,
3H), 3.78 (s, 3H), 6.79 (d, J = 8.7 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.92-6.98 (m, 2H),
7.35 (s, 1H), 8.26 (s, 1H), 9.50 (d, J = 7.2 Hz, 1H); 13C{H}NMR (75 MHz, CDCl3): δ
21.4, 27.7, 55.5, 111.9, 114.2, 118.6, 120.1, 122.8, 124.1, 129.3, 138.9, 143.9, 148.6,
150.7, 151.9, 152.8, 194.7; IR (KBr): ν = 3032, 2973, 2868, 1668, 1620, 1530, 1473,
1428, 1308, 1246, 1124, 760, 638 cm-1; HRMS (ESI) calcd for C18H17ClN3O2 [M+H]+:
342.1004, found: 342.1007.
1-(7-Chloro-4-((2-methoxyphenyl)imino)-8-methyl-4H-pyrido[1,2-a]pyrimidin-3-yl)
ethanone (4g): Prepared from 3g (359 mg, 1.0 mmol) according to the general
procedure B. The crude product was purified by flash column chromatography (silica
gel, petroleum ether/ethyl acetate as the eluent = 3:2) to give 4g as a reddish yellow
solid (326 mg, 96%). mp 155-157 oC; 1H NMR (300 MHz, CDCl3): δ 1.88 (s, 3H), 2.52
(s, 3H), 3.79 (s, 3H), 6.87-6.95 (m, 3H), 6.99-7.10 (m, 1H), 7.38 (s, 1H), 8.12 (s, 1H),
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9.65 (s, 1H); C{H}NMR (100 MHz, CDCl3): δ 19.9, 27.9, 55.2, 111.2, 115.4, 120.7,
121.1, 123.9, 125.3, 126.0, 127.5, 137.1, 142.8, 148.7, 149.8, 150.7, 151.9, 195.4; IR
(KBr): ν = 3086, 2933, 2879, 1687, 1614, 1545, 1483, 1418, 1305, 1189, 1012, 875, 612
cm-1; HRMS (ESI) calcd for C18H17ClN3O2 [M+H]+: 342.1004, found: 342.1010.
1-(7-Chloro-4-((4-chlorophenyl)imino)-8-methyl-4H-pyrido[1,2-a]pyrimidin-3-yl)
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ethanone (4h): Prepared from 3h (364 mg, 1.0 mmol) according to the general
procedure B. The crude product was purified by flash column chromatography (silica
gel, petroleum ether/ethyl acetate as the eluent = 3:2) to give 4h as a reddish yellow
solid (315 mg, 91%). mp 164-166 oC; 1H NMR (300 MHz, CDCl3): δ 1.92 (s, 3H), 2.53
(s, 3H), 6.82 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 8.18 (s, 1H),
9.54 (s, 1H); 13C{H}NMR (75 MHz, CDCl3): δ 20.1, 28.3, 113.6, 120.7 (2C), 125.4,
126.5, 127.0, 128.0, 129.6 (2C), 143.7, 147.4, 149.5, 150.8, 154.0, 195.7; IR (KBr): ν =
3092, 2921, 2850, 1683, 1470, 1610, 1470, 1373, 1254, 1095, 600 cm-1; HRMS (ESI)
calcd for C17H14Cl2N3O [M+Na]+: 346.0508, found: 346.0505.
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1-(7-Chloro-8-methyl-4-(phenylimino)-4H-pyrido[1,2-a]pyrimidin-3-yl)ethanone
(4i): Prepared from 3i (330 mg, 1.0 mmol) according to the general procedure B. The
crude product was purified by flash column chromatography (silica gel, petroleum
ether/ethyl acetate as the eluent = 3:2) to give 4i as a reddish yellow solid (281 mg, 90
%). mp 156-158 oC; 1H NMR (300 MHz, CDCl3): δ 1.81 (s, 3H), 2.52 (s, 3H), 6.89 (d, J
= 7.5 Hz, 2H), 7.01 (t, J = 7.5 Hz, 1H), 7.30 (t, J = 7.5 Hz, 2H), 7.39 (s, 1H), 8.12 (s,
1H), 9.57 (s, 1H); 13C{H}NMR (75 MHz, CDCl3): δ 20.0, 28.4, 114.1, 119.6 (2C),
123.3, 125.4, 126.2, 127.0, 129.6 (2C), 143.5, 148.6, 149.2, 150.9, 153.5, 196.2; IR
(KBr): ν = 3102, 2946, 2872, 1665, 1618, 1513, 1474, 1426, 1368, 1247, 1134, 626 cm-1;
HRMS (ESI) calcd for C17H15ClN3O [M+H]+: 312.0898, found: 312.0901.
1-(8-Methoxy-4-((2-methoxyphenyl)imino)-4H-pyrido[1,2-a]pyrimidin-3-yl)ethanoe
(4j): Prepared from 3j (341 mg, 1.0 mmol) according to the general procedure B. The
crude product was purified by flash column chromatography (silica gel, petroleum
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142-144 C; H NMR (400 MHz, CDCl3): δ 1.87 (s, 3H), 3.80 (s, 3H), 3.98 (s, 3H),
6.74-6.78 (m, 2H), 6.83-6.91 (m, 3H), 6.97-7.02 (m, 1H), 8.12 (s, 1H), 9.51 (d, J = 7.6
Hz, 1H); 13C{H}NMR (100 MHz, CDCl3): δ 27.7, 55.3, 56.4, 102.1, 109.9, 111.3, 114.0,
120.2, 121.1, 123.6, 131.4, 137.8, 143.9, 150.0, 153.1, 154.4, 166.5, 195.4; IR (KBr): ν
= 3064, 2946, 1692, 1638, 1588, 1483, 1369, 1237, 782, 712 cm-1; HRMS (ESI) calcd
for C18H18N3O3 [M+H]+: 324.1343, found: 324.1345.
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1-(4-((4-Chlorophenyl)imino)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-3-yl)ethanone
(4k): Prepared from 3k (346 mg, 1.0 mmol) according to the general procedure B. The
crude product was purified by flash column chromatography (silica gel, petroleum
ether/ethyl acetate as the eluent = 3:2) to give 4k as a yellow solid (270 mg, 82%). mp
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158-160 C; H NMR (400 MHz, CDCl3): δ 1.92 (s, 3H), 3.99 (s, 3H), 6.78-6.82 (m,
4H), 7.23 (d, J = 8.4 Hz, 2H), 8.18 (s, 1H), 9.39 (d, J = 7.6 Hz, 1H); 13C{H}NMR (100
MHz, CDCl3): δ 28.1, 56.5, 102.2, 110.3, 112.0, 120.7 (2C), 127.5, 129.4 (2C), 130.9,
144.7, 147.9, 154.4, 154.8, 166.9, 195.5; IR (KBr): ν = 3074, 2982, 2942, 2838, 1656,
1607, 1517, 1445, 1387, 1238, 1126, 1008, 744 cm-1; HRMS (ESI) calcd for
C17H14ClN3NaO2 [M+Na]+: 350.0667, found: 350.0663.
1-(8-Methoxy-4-(phenylimino)-4H-pyrido[1,2-a]pyrimi-din-3-yl)ethanone
(4l):
Prepared from 3l (311 mg, 1.0 mmol) according to the general procedure B. The crude
product was purified by flash column chromatography (silica gel, petroleum ether/ethyl
acetate as the eluent = 3:2) to give 4l as a yellow solid (228 mg, 78%). mp 153-154 oC;
1H NMR (300 MHz, CDCl3): δ 1.82 (s, 3H), 3.99 (s, 3H), 6.77-6.79 (m, 2H), 6.89 (d, J =
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7.5 Hz, 2H), 6.99 (t, J = 7.5 Hz, 1H), 7.29 (t, J = 7.5 Hz, 2H), 8.13 (s, 1H), 9.43 (d, J =
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7.2 Hz, 1H); C{H}NMR (75 MHz, CDCl3): δ 28.2, 56.4, 102.1, 110.1, 112.6, 119.6
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(2C), 122.8, 129.4 (2C), 130.9, 144.5, 149.1, 154.4, 154.5, 166.7, 196.1; IR (KBr): ν =
3089, 2979, 2938, 1656, 1627, 1561, 1461, 1414, 1186, 1017, 699 cm-1; HRMS (ESI)
calcd for C17H15N3NaO2 [M+Na]+: 316.1056, found: 316.1054.
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1-(9-Methyl-4-(phenylimino)-4H-pyrido[1,2-a]pyrimidi-n-3-yl)ethanone
(4m):
Prepared from 3m (295 mg, 1.0 mmol) according to the general procedure B. The crude
product was purified by flash column chromatography (silica gel, petroleum ether/ethyl
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acetate as the eluent = 3:2) to give 4m as a yellow (252 mg, 91%). mp 125-126 C; H
NMR (300 MHz, CDCl3): δ 1.86 (s, 3H), 2.58 (s, 3H), 6.91 (d, J = 7.8 Hz, 2H),
6.99-7.08 (m, 2H), 7.31 (t, J = 8.1 Hz, 2H), 7.67 (d, J = 6.6 Hz, 1H), 8.24 (s, 1H), 9.45
13
(d, J = 7.2 Hz, 1H); C{H}NMR (75 MHz, CDCl3): δ 18.4, 28.3, 114.1, 115.3, 119.5
(2C), 123.1, 127.8, 129.6 (2C), 134.2, 137.1, 145.1, 149.2, 151.9, 152.6, 196.5; IR (KBr):
ν = 3131, 2964, 2938, 2871, 1678, 1632, 1561, 1488, 1425, 1173, 1024, 776 cm-1;
HRMS (ESI) calcd for C17H15N3NaO [M+Na]+: 300.1107, found: 300.1110.
1-(4-((2-Methoxyphenyl)imino)-4H-pyrido[1,2-a]pyrim-idin-3-yl)ethanone
(4n):
Prepared from 3n (311 mg, 1.0 mmol) according to the general procedure B. The crude
product was purified by flash column chromatography (silica gel, petroleum ether/ethyl
acetate as the eluent = 3:2) to give 4n as a yellow solid (258 mg, 88%). mp 122-124 oC;
1H NMR (300 MHz, CDCl3): δ 1.90 (s, 3H), 3.80 (s, 3H), 6.88-6.95 (m, 3H), 6.99-7.05
(m, 1H), 7.13 (td, J1 =6.9 Hz, J2 = 1.5 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.77 (ddd, J1
=8.7 Hz, J2 = 6.9 Hz, J3 = 1.5 Hz, 1H), 8.17 (s, 1H), 9.62 (d, J = 6.3 Hz, 1H);
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13C{H}NMR (75 MHz, CDCl3): δ 27.8, 55.2, 111.2, 115.5, 115.6, 120.4, 121.1, 123.8,
125.7, 130.0, 137.4, 137.8, 143.8, 149.8, 151.9, 152.2, 195.6; IR (KBr): ν = 3011, 2976,
2914, 2863, 1642, 1614, 1514, 1437, 1382, 1216, 1110, 772 cm-1; HRMS (ESI) calcd for
C17H15N3NaO2 [M+Na]+: 316.1056, found: 316.1059.
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1-(4-(p-Tolylimino)-4H-pyrido[1,2-a]pyrimidin-3-yl)ethanone (4o): Prepared from
3o (295 mg, 1.0 mmol) according to the general procedure B. The crude product was
purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate as the
eluent = 3:2) to give 4o as a yellow solid (251 mg, 91 %). mp 121-123 oC; 1H NMR (300
MHz, CDCl3): δ 1.83 (s, 3H), 2.30 (s, 3H), 6.81 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.7 Hz,
2H), 7.09-7.14 (m, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.74-7.80 (m, 1H), 8.15 (s, 1H), 9.51
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(d, J = 6.3 Hz, 1H); C{H}NMR (75 MHz, CDCl3): δ 20.9, 28.4, 114.5, 115.7, 119.3
(2C), 125.8, 129.6, 130.2 (2C), 132.6, 138.0, 144.4, 146.2, 152.5, 153.3, 196.5; IR (KBr):
ν = 3109, 2988, 2936, 1653, 1612, 1561, 1498, 1491, 1362, 1242, 1156, 788 cm-1;
HRMS (ESI) calcd for C17H16N3O [M+H]+: 278.1288, found: 278.1285.
1-(4-((3-Nitrophenyl)imino)-4H-pyrido[1,2-a]pyrimidin-3-yl)ethanone
(4p):
Prepared from 3p (326 mg, 1.0 mmol) according to the general procedure B. The crude
product was purified by flash column chromatography (silica gel, petroleum ether/ethyl
acetate as the eluent = 3:2) to give 4p as a reddish yellow solid (252 mg, 82%). mp
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99-101 C; H NMR (300 MHz, CDCl3): δ 2.10 (s, 3H), 7.19-7.24 (m, 2H), 7.46 (t, J =
7.8 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.67 (t, J = 2.1 Hz, 1H), 7.82-7.90 (m, 2H), 8.40 (s,
1H), 9.58 (d, J = 6.6 Hz, 1H); 13C{H}NMR (75 MHz, CDCl3): δ 28.0, 112.6, 113.7,
116.7, 117.4, 125.8, 126.2, 129.6, 130.1, 138.7, 145.0, 149.0, 150.7, 152.3, 154.8, 194.9;
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IR (KBr): ν = 3018, 2991, 2927, 1682, 1643, 1538, 1406, 1210, 869, 767 cm-1; HRMS
(ESI) calcd for C16H12N4NaO3 [M+Na]+: 331.0802, found: 331.0799.
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1-(4-(Benzylimino)-4H-pyrido[1,2-a]pyrimidin-3-yl)ethanone (4q): Prepared from 3q
(295 mg, 1.0 mmol) according to the general procedure B. The crude product was
purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate as the
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eluent = 3:2) to give 4q as a yellow solid (208 mg, 75%). mp 65-67 C; H NMR (300
MHz, CDCl3): δ 2.55 (s, 3H), 4.20 (s, 2H), 7.07 (td, J1 =7.2 Hz, J2 = 1.4 Hz, 1H), 7.23 (t,
J = 7.2 Hz, 1H), 7.32 (t, J = 7.2 Hz, 2H), 7.40 (d, J = 7.2 Hz, 2H), 7.47 (d, J = 8.4 Hz,
1H), 7.72-7.79 (ddd, J1 =8.4 Hz, J2 = 7.2 Hz, J3 = 1.4 Hz, 1H), 8.45 (s, 1H), 9.36 (d, J =
13
7.2 Hz, 1H); C{H}NMR (75 MHz, CDCl3): δ 26.8, 55.5, 111.9, 115.7, 124.9, 126.4,
127.5 (2C), 128.6 (2C), 131.0, 138.5, 141.6, 143.6, 152.4, 154.9, 193.4; IR (KBr): ν =
3023, 2948, 2905, 2874, 1673, 1630, 1545, 1470, 1410, 1352, 1283, 1138, 768, 714
cm-1; HRMS (ESI) calcd for C17H16N3O [M+H]+: 278.1288, found: 278.1290.
1-(4-(Butylimino)-4H-pyrido[1,2-a]pyrimidin-3-yl)ethanone (4r): Prepared from 3r
(261 mg, 1.0 mmol) according to the general procedure B. The crude product was
purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate as the
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eluent = 3:2) to give 4r as a yellow solid (165 mg, 68%). mp 58-59 C; H NMR (300
MHz, CDCl3): δ 0.90 (t, J = 7.2 Hz, 3H), 1.41-1.46 (m, 2H), 1.61-1.66 (m, 2H), 2.50 (s,
3H), 2.95 (t, J = 6.6 Hz, 2H), 7.02 (t, J = 6.9 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.71 (t, J
= 8.7 Hz, 1H), 8.35 (s, 1H), 9.21 (d, J = 7.2 Hz, 1H); 13C{H}NMR (75 MHz, CDCl3): δ
13.7, 19.6, 30.5, 31.2, 65.5, 117.4, 127.0, 128.8, 130.9, 132.3, 139.2, 158.4, 167.7, 196.4;
IR (KBr): ν = 3014, 2928, 2901, 2864, 1686, 1628, 1578, 1447, 1286, 1208, 1012, 868,
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756 cm-1; HRMS (ESI) calcd for C14H17N3NaO [M+Na]+: 266.1264, found: 266.1266.
(4-((2-Methoxyphenyl)imino)-4H-pyrido[1,2-a]pyrimid-in-3-yl)(phenyl)methanone
(4s): Prepared from 3s (373 mg, 1.0 mmol) according to the general procedure B. The
crude product was purified by flash column chromatography (silica gel, petroleum
ether/ethyl acetate as the eluent = 3:2) to give 4s as a yellow solid (315 mg, 89%). mp
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131-133 C; H NMR (300 MHz, CDCl3): δ 3.51 (s, 3H), 6.46 (d, J = 8.1 Hz, 1H),
6.58-6.66 (m, 2H), 6.76-6.82 (m, 1H), 7.15 (t, J = 6.9 Hz, 1H), 7.25 (t, J = 7.5 Hz, 2H),
7.38-7.46 (m, 3H), 7.58 (d, J = 9.0 Hz, 1H), 7.79 (ddd, J1 =8.4 Hz, J2 = 6.9 Hz, J3 = 1.8
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Hz, 1H), 8.04 (s,1H), 9.64 (d, J = 7.2 Hz, 1H); C{H}NMR (75 MHz, CDCl3): δ 54.8,
110.4, 113.7, 115.6, 120.7, 121.0, 123.5, 125.9, 127.9 (2C), 128.3 (2C), 130.0, 131.9,
136.9, 136.9, 137.7, 144.7, 149.8, 152.4, 153.0, 192.0; IR (KBr): ν = 3030, 2960, 2941,
2837, 1642, 1626, 1471, 1342, 1244, 1171, 1157, 868, 721 cm-1; HRMS (ESI) calcd for
C22H18N3O2 [M+H]+: 356.1394, found: 356.1397.
(4-((2-Chlorophenyl)imino)-8-methyl-4H-pyrido[1,2-a]pyrimidin-3-yl)(phenyl)
methanone (4t): Prepared from 3t (392 mg, 1.0 mmol) according to the general
procedure B. The crude product was purified by flash column chromatography (silica
gel, petroleum ether/ethyl acetate as the eluent = 3:2) to give 4t as a reddish yellow solid
(310 mg, 83%). mp 147-149 oC; 1H NMR (300 MHz, CDCl3): δ 2.54 (s, 3H), 6.69-6.73
(m, 2H), 6.91-7.06 (m, 3H), 7.26 (t, J = 6.6 Hz, 2H), 7.40-7.45 (m, 4H), 8.11 (s, 1H),
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9.56 (d, J = 7.5 Hz, 1H); C{H}NMR (75 MHz, CDCl3): δ 21.4, 111.8, 118.7, 120.1,
123.3, 124.4, 126.3, 127.1, 128.2 (2C), 128.2 (2C), 129.0, 129.8, 132.3, 137.1, 145.1,
145.6, 150.7, 152.1, 155.1, 192.3; IR (KBr): ν = 3032, 2956, 2936, 2857, 1671, 1628,
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